Apoptosis promoters

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic protein family members, compositions containing the compounds and uses of the compounds for preparing medicaments for treating diseases during which occurs expression one or more than one of an anti-apoptotic protein family member.

This application is a continuation of U.S. patent application Ser. No.11/127,940, filed May 12, 2005 , now U.S. Pat. No. 7,767,684, which is acontinuation-in-part of U.S.patent application Ser. No. 10/988,338,filed Nov. 12, 2004, now abandoned, which claims priority to U.S.Provisional Application 60/519,695, filed Nov. 13, 2003, thespecifications of which are hereby incorporated by reference into thisapplication.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity ofanti-apoptotic protein family members, compositions containing thecompounds, and methods of treating diseases during which are expressedof one or more than one of an anti-apoptotic protein family member.

BACKGROUND OF THE INVENTION

Anti-apoptotic protein family members are associated with a number ofdiseases. There is therefore an existing need in the therapeutic artsfor compounds which inhibit the activity of one of more than one of ananti-apoptotic protein family member.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as inhibitors one or more than one anti-apoptoticprotein family member, the compounds having formula (I)

wherein A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole; and

one or two or each of A², D¹ and E¹ are independently selected R¹, OR¹,SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹, N(CH₃)C(O)N(CH₃)R¹,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and theremainder are independently selected H, F, Cl, Br, I, CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆ -alkynyl;

R² is phenyl which is unfused or fused with arene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with arene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three) independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(8A);

R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with arene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with arene,heteroarene or R^(14A); R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with arene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with arene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

Z¹ is R²⁶ or R²⁷, each of which is substituted with R²⁸, R²⁹ or R³⁰,each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷;

R²⁶ is phenyl which is unfused or fused with arene or heteroarene;

R²⁷ is heteroarene which is unfused or fused with arene or heteroarene;

R²⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene

R²⁹ is heteroaryl or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with arene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with arene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with arene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with arene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with arene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five independently selected R⁵⁰, OR⁵⁰, SR⁵⁰,S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰,N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰,C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃,C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, OH, (O), N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl or R^(52A); R^(52A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53A); R^(53A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

R⁵⁶ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

Still another embodiment pertains to compounds having formula (I)-a

or therapeutically acceptable salts, prodrugs or salts of prodrugsthereof, wherein

R^(5a) is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is N or C(A²);

A² is H, F, CN, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is R¹, OR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹;

D¹ is H, F, Cl or CF₃;

E¹ is H, F or Cl;

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole;

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl, C₆-alkyl;

R² is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R³ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R⁴ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N;

R⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl, C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl, C₆-alkenyl, C₃-alkynyl,C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶, R⁷, OR⁷,SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷,NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-spiroalkyl, C₃-spiroalkyl, C₄-spiroalkyl or C₅-spiroalkyl, eachof which is unsubstituted or substituted with OH, (O), N₃, CN, CF₃,CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine, 1,2,3-triazole or R^(8A);

R^(8A) is C₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane,C₄-cycloalkene, C₅-cycloalkene or C₆-cycloalkene, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N;

R⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R¹⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl,C₈-cycloalkenyl, C₉-cycloalkenyl, C₁₀-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N;

R¹¹ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₂-alkynyl,C₃-alkynyl, C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which isunsubstituted or substituted with one or two or three independentlyselected R¹², OR¹², NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH,(O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine, 1,2,3-triazole or R^(13A);

R^(13A) is C₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane,C₄-cycloalkene, C₅-cycloalkene or C₆-cycloalkene, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N;

R¹⁴ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl, 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole; pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R¹⁵ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N;

R¹⁶ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₃-alkynyl,C₄-alkynyl, C₅-alkynyl or C₆-alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R¹⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R²⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl,C₈-cycloalkenyl, C₉-cycloalkenyl, C₁₀-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N;

R²¹ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₂-alkynyl,C₃-alkynyl, C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which isunsubstituted or substituted with one or two or three independentlyselected R²², OR²², NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH,(O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R²⁴ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl, 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R²⁵ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N;

Z¹ is R²⁶ or R²⁷, each of which is substituted with R²⁸, R²⁹ or R³⁰,each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R NHR³⁷, NHR³⁷ orN(R³²)R³⁷;

R²⁶ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R²⁷ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R²⁸ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R²⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R³⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl,C₁₁-cycloalkyl, C₁₂-cycloalkyl, C₁₃-cycloalkyl, C₁₄-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl,C₈-cycloalkenyl, C₉-cycloalkenyl or C₁₀-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N;

R³¹ and R³¹, are independently F, Cl, Br, C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl or C₆-alkyl or are taken together and areC₂-spiroalkyl, C₃-spiroalkyl, C₄-spiroalkyl or C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R³⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl or C₆-alkyl,each of which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R³⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R⁴⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl,C₆-cycloalkenyl, C₇-cycloalkenyl or C₈-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine, 1,2,3-triazole or R^(42A);

R^(42A) is C₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane,C₄-cycloalkene, C₅-cycloalkene or C₆-cycloalkene, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N;

R⁴³ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R⁴⁴ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N, and each of which is unfused or fusedwith benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole;

R⁴⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₂-alkynyl,C₃-alkynyl, C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which isunsubstituted or substituted with one or two independently selected R⁴⁶,OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH,N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R⁴⁸ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;

R⁴⁹ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N;

wherein the moieties represented by B¹ and Y¹ together are substitutedwith C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl, eachof which is substituted with one or two independently selected SR⁵⁵ orN(R⁵⁵)₂ substituents, wherein R⁵⁵ is independently selected phenyl,C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl;

the moieties represented by R², R³ and R⁴ are unsubstituted orsubstituted with one or two independently selected R⁵⁰, OR⁵⁰, SR⁵⁰,SO₂R⁵⁰, CO(O)R⁵⁰ or OCF₃ substituents, wherein R⁵⁰ is phenyl, C₁-alkyl,C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl;

the moieties represented by R⁸, R⁹ and R¹⁰ are unsubstituted orsubstituted with one or two independently selected R⁵⁰, OR⁵⁰,C(O)NHSO₂R⁵⁰, CO(O)R⁵⁰, C(O)R⁵⁰, C(O)OH, C(O)NHOH, OH, NH₂, F, Cl, Br orI substituents, wherein R⁵⁰ is phenyl, tetrazolyl or R⁵⁴, wherein R⁵⁴ isC₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl; C₅-alkyl or C₆-alkyl, each ofwhich is unsubstituted or substituted with phenyl;

the moieties represented by R²⁶ and R²⁷ are further unsubstituted orsubstituted with one or two independently selected F, Br, Cl or Isubstituents;

the moieties represented by R²⁸, R²⁹ and R³⁰ are further unsubstitutedor substituted with OR⁵⁴, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl or C₆ -alkyl, each of which is unsubstituted orsubstituted with R⁵⁶, wherein R⁵⁶ is C₃-cycloalkyl, C₄-cycloalkylC₅-cycloalkyl or C₆-cycloalkyl, each having one or two CH₂ moietiesreplaced with independently selected O or NH and one CH moietyunreplaced or replaced with N;

the moieties represented by R³⁸, R³⁹ and R⁴⁰ are unsubstituted orsubstituted with one or two independently selected R⁵⁴ F, Br, Cl or Isubstituent, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅-alkyl or C₆ -alkyl; and

the moieties represented by R⁴², R⁴³, R⁴⁴ and R⁴⁵ are unsubstituted orsubstituted with one or two independently selected R⁵⁰, OR⁵⁰, SR⁵⁰,N(R⁵⁰)₂, SO₂R⁵⁰, CN, CF₃, F, Cl, Br or I substituents, wherein R⁵⁰ isphenyl or R⁵⁴, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅-alkyl or C₆-alkyl, each of which is unsubstituted or substituted withN(R⁵⁵)₂ or R⁵⁶, wherein R⁵⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅-alkyl or C₆-alkyl and R⁵⁶ is C₃-cycloalkyl, C₄-cycloalkyl,C₅-cycloalkyl or C₆-cycloalkyl, each having one CH₂ moiety unreplaced orreplaced with independently selected O, C(O), S, S(O), SO₂ or NH and oneor two CH moieties unreplaced or replaced with N.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²);

A² is H, F, CN, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹;

D¹ is H, F, Cl or CF₃;

E¹ is H, F or Cl;

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, CF₃, OCF₃, NH₂, C(O)NH₂ or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole;

R¹ is R², R³, R⁴ or R⁵;

R is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl, C₆-alkyl;

R² is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R³ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene;

R⁴ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N;

R⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl, C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl, C₆-alkenyl, C₃-alkynyl,C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶, R⁷, OR⁷,SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷,NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-spiroalkyl, C₃-spiroalkyl, C₄-spiroalkyl or C₅-spiroalkyl, eachof which is unsubstituted or substituted with OH, (O), N₃, CN, CF₃,CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine, 1,2,3-triazole or R^(8A);

R^(8A) is C₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane,C₄-cycloalkene, C₅-cycloalkene or C₆-cycloalkene, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N;

R⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene;

R¹⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl,C₈-cycloalkenyl, C₉-cycloalkenyl, C₁₀-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N;

R¹¹ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₂-alkynyl,C₃-alkynyl, C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which isunsubstituted or substituted with one or two or three independentlyselected R¹², OR¹², NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH,(O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine, 1,2,3-triazole or R^(13A);

R^(13A) is C₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane,C₄-cycloalkene, C₅-cycloalkene or C₆-cycloalkene, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N;

R¹⁴ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl, 1,2,3-triazolyl, each of which is unfused or fused withbenzene;

R¹⁵ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N;

R¹⁶ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₃-alkynyl,C₄-alkynyl, C₅-alkynyl or C₆-alkynyl;

Z¹ is R²⁶ or R²⁷, each of which is substituted with R²⁸, R²⁹ or R³⁰,each of which is substituted with Cl, Br, CH₂R³⁷, C(R³¹)(R^(31A))(R³⁷),C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷ or NHR³⁷;

R²⁶ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R²⁷ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene;

R²⁸ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R²⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene;

R³⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl,C₁₁-cycloalkyl, C₁₂-cycloalkyl, C₁₃-cycloalkyl, C₁₄-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl,C₈-cycloalkenyl, C₉-cycloalkenyl or C₁₀-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N;

R³¹ and R^(31A) are independently F, Cl, Br, C₁-alkyl, C₂-alkyl,C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl or are taken together and areC₂-spiroalkyl, C₃-spiroalkyl, C₄-spiroalkyl or C₅-spiroalkyl;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R³⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene;

R⁴⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl,C₆-cycloalkenyl, C₇-cycloalkenyl or C₈-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine, 1,2,3-triazole or R^(42A);

R^(42A) is C₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane,C₄-cycloalkene, C₅-cycloalkene or C₆-cycloalkene, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N;

R⁴³ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene;

R⁴⁴ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N, and each of which is unfused or fusedwith benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole;

R⁴⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl,C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₂-alkynyl,C₃-alkynyl, C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which isunsubstituted or substituted with one or two independently selected R⁴⁶,OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH,N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole;

R⁴⁸ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene;

R⁴⁹ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N;

wherein the moieties represented by B¹ and Y¹ together are substitutedwith C₂-alkyl, C₃-alkyl or C₄-alkyl, each of which is substituted withone or two independently selected SR⁵⁵ or N(R⁵⁵)₂ substituents, whereinR⁵⁵ is independently selected phenyl or C₁-alkyl;

the moieties represented by R², R³ and R⁴ are unsubstituted orsubstituted with one or two independently selected R⁵⁰, OR⁵⁰, SR⁵⁰,SO₂R⁵⁰, CO(O)R⁵⁰ or OCF₃ substituents, wherein R⁵⁰ is phenyl, C₁-alkyl,C₂-alkyl, C₃-alkyl or C₄-alkyl;

the moieties represented by R⁸, R⁹ and R¹⁰ are unsubstituted orsubstituted with one or two independently selected R⁵⁰, OR⁵⁰,C(O)NHSO₂R⁵⁰, CO(O)R⁵⁰, C(O)R⁵⁰, C(O)OH, C(O)NHOH, OH, NH₂, F, Cl, Br orI substituents, wherein R⁵⁰ is phenyl, tetrazolyl or R⁵⁴, wherein R⁵⁴ isC₁-alkyl, C₂-alkyl or C₃-alkyl, each of which is unsubstituted orsubstituted with phenyl;

the moieties represented by R²⁶ and R²⁷ are further unsubstituted orsubstituted with one or two independently selected F, Br, Cl or Isubstituents;

the moieties represented by R²⁸, R²⁹ and R³⁰ are further unsubstitutedor substituted with OR⁵⁴, wherein R⁵⁴ is C₁-alkyl or C₂-alkyl, each ofwhich is unsubstituted or substituted with N(R⁵⁵)₂ or R⁵⁶, wherein R⁵⁵is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl, and R⁵⁶is C₅-cycloalkyl or C₆-cycloalkyl, each having one or two CH₂ moietiesreplaced with independently selected O or NH and one CH moietyunreplaced or replaced with N;

the moieties represented by R³⁸, R³⁹ and R⁴⁰ are unsubstituted orsubstituted with one or two independently selected C₁-alkyl, F, Br, Clor I substituents; and

the moieties represented by R⁴², R⁴³, R⁴⁴ and R⁴⁵ are unsubstituted orsubstituted with one or two independently selected R⁵⁰, OR⁵⁰, SR⁵⁰,N(R⁵⁰)₂, SO₂R⁵⁰, CN, CF₃, F, Cl, Br or I substituents, wherein R⁵⁰ isphenyl or R⁵⁴, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl or C₃-alkyl, each ofwhich is unsubstituted or substituted with N(C₁-alkyl)₂ or C₆-cycloalkylhaving one CH₂ moiety replaced with O and one CH moiety replaced with N.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²);

A² is H, F, CN, C(O)OH, C(O)NH₂ or C(O)OCH₃;

B¹ is R¹, OR¹, NHR¹, N(R¹)₂ or NR¹C(O)N(R¹)₂;

D¹ is H, F, Cl or CF₃;

E¹ is H, F or Cl;

Y¹ is H, CN, NO₂, F, Cl, CF₃, OCF₃, NH₂, C(O)NH₂, or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole;

R¹ is phenyl, pyrrolyl, cyclopentyl, cyclohexyl, piperidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl or R⁵;

R⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl or C₆-alkyl,each of which is unsubstituted or substituted with one or two or threeindependently selected C₄-spiroalkyl, C₅-spiroalkyl, R⁷, OR⁷, SR⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷,NHC(O)OR⁷, NHC(O)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, OH, C(O)OH or NH₂substituents;

R⁷ is phenyl, furanyl, imidazolyl, pyridinyl, tetrazolyl, thiazolyl,thienyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl, 1,3-benzothiazole,cyclopropyl, cyclobutyl, cyclohexyl, azetidinyl, morpholinyl,piperazinyl, piperidinyl, thiomorpholinyl, thiomorpholinyl sulfone7-azabicyclo[2.2.1]heptanyl, 8-azabicyclo[3.2.1]octanyl,4,5-dihydro-1H-imidazolyl 2-oxa-5-azabicyclo[2.2.1]heptanyl,1,4,5,6-tetrahydropyrimidinyl or R¹¹;

R¹¹ is C₁-alkyl, C₂-alkyl, C₃-alkyl or C₄-alkyl, each of which isunsubstituted or substituted with one or two or three independentlyselected R¹², OR¹², N(R¹²)₂, C(O)N(R¹²)₂, OH, C(O)OH, NH₂, CF₃, F, Cl,Br or I substituents;

R¹² is 1,3-benzodioxolyl, pyridinyl, morpholinyl or C₁-alkyl;

Z¹ is phenyl or pyridinyl, each of which is substituted withcyclohexenyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl oroctahydropyrrolo[3,4-c]pyrrolyl, each of which is substituted withCH₂R³⁷, C(C₂-spiroalkyl)(R³⁷) or C(O)R³⁷;

R³⁷ is phenyl, naphthyl, imidazolyl, pyrazolyl, pyridinyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl or3,6-dihydro-2H-pyranyl, each of which is substituted with F, Cl, Br, I,R⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹ or SR⁴¹;

R⁴⁵ is phenyl, naphthyl, cyclohexyl, morpholinyl, piperidinyl, thienyl,pyridinyl, quinolinyl, benzofuranyl, 1,3-benzodioxolyl, isoindolinyl,1,3-oxazolidin-2-onyl or R⁴⁵;

R⁴⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl or C₄-alkyl, each of which isunsubstituted or substituted with phenyl;

wherein the moieties represented by B¹ and Y¹ together are substitutedwith C₂-alkyl, C₃-alkyl or C₄-alkyl, each of which is substituted withone or two independently selected SR⁵⁵ or N(R⁵⁵)₂ substituents, whereinR⁵⁵ is independently selected phenyl or C₁-alkyl;

the moieties represented by R¹ are unsubstituted or substituted with oneor two independently selected R⁵⁰, OR⁵⁰, SR⁵⁰, SO₂R⁵⁰, CO(O)R⁵⁰ or OCF₃substituents, wherein R⁵⁰ is phenyl, C₁-alkyl, C₂-alkyl, C₃-alkyl orC₄-alkyl;

the moieties represented by R⁷ are unsubstituted or substituted with oneor two independently selected R⁵⁰, OR⁵⁰, C(O)NHSO₂R⁵⁰, CO(O)R⁵⁰,C(O)R⁵⁰, C(O)OH, C(O)NHOH, OH, NH₂, F, Cl, Br or I substituents, whereinR⁵⁰ is phenyl, tetrazolyl or R⁵⁴, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl orC₃-alkyl, each of which is unsubstituted or substituted with phenyl;

the phenyl and pyridinyl moieties of Z¹ are further unsubstituted orsubstituted with one or two independently selected F, Br, Cl or Isubstituents;

the cyclohexenyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyland octahydropyrrolo[3,4-c]pyrrolyl moieties of Z¹ are furtherunsubstituted or substituted with OR⁵⁴, wherein R⁵⁴ is C₁-alkyl orC₂-alkyl, each of which is unsubstituted or substituted withN(C₁-alkyl)₂, morpholinyl, piperidinyl or piperidinyl;

the moieties represented by R³⁷ are unsubstituted or substituted withone or two independently selected C₁-alkyl, F, Br, Cl or I substituents;

and

the moieties represented by R⁴¹ are unsubstituted or substituted withone or two independently selected R⁵⁰, OR⁵⁰, SR⁵⁰, N(R⁵⁰)₂, SO₂R⁵⁰, CN,CF₃, F, Cl, Br or I substituents, wherein R⁵⁰ is phenyl or R⁵⁴, whereinR⁵⁴ is C₁-alkyl, C₂-alkyl or C₃-alkyl, each of which is unsubstituted orsubstituted with N(C₁-alkyl)₂ or morpholinyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoro-ethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-62-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)-propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy, (1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(1,3-benzodioxol-5-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(benzofuran-2-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-bromocyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-bromocyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-(4-bromophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclohept-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(1-(2-(4-chlorophenyl)cyclohex-1-en-1-ylmethyl)-1,2, 3,6-tetrahydropyridin-4-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclooct-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)-piperazin-1-yl)phenylcarbonyl,4-(1-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylmethyl,4-(4-(2-(4-chlorophenyl)naphth-3-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)pyridin-3-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(4-chlorophenyl)pyridin-4-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)pyridin-5-yl)methyl)-piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylcarbonyl) piperazin-1-yl)phenylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylcycloprop-1-yl)piperazin-1-yl)phenylcarbonyl or4-(4-(2-(4-chlorophenyl)phenylmethyl)cyclohex-1-en-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)-pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethyl-pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethyl-pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy, (1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino; D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN,NO₂, F, Cl, CF₃, OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(5-(2-(4-chlorophenyl)phenylmethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenylcarbonyl,4-(4-(2-(4 -chlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)-4-methoxypiperidin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)-piperazin-1-yl)-3,5-difluorophenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-2-fluorophenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-3-fluorophenylcarbonyl,2-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)pyridin-5-ylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylmethyl)piperidin-4-yl)phenylcarbonyl,5-(4-(2-(4-chlorophenyl)phenylmethyl)-piperazin-1-yl)pyridin-2-ylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbonyl,4-(4-(2-(cyclohex-1-ylamino)phenylmethyl)piperazin-1-yl)phenylcarbonyl4-(4-(2-cyclohex-1-ylphenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3-cyanophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2,4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3,4-dichlorophenyl)phenylmethyl)piperazin-1 -yl)phenylcarbonyl,4-(4-(2-(2,4-difluorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-(1,3-dihydro-2H-isoindol-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(1,1-dimethylethoxycarbonylamino)phenyl)piperazin-1-yl)phenylcarbonyl,4-(2-(4-(2-(dimethylamino)ethoxy)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor 4-(4-(3-(dimethylamino)phenyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)-pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethyl-pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy, (1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino; D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y is H, CN,NO₂, F, Cl, CF₃, OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(2-(4-(dimethylamino)phenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(dimethylamino)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-(dimethylamino)phenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)-3-fluorophenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-fluorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(2-(isopropylamino)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(isopropylsulfanyl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methoxyphenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3 -methoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methoxyphenyl)phenylmethyl)piperazin-1 -yl)phenylcarbonyl,4-(4-((2-(4-methoxyphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-methoxy-4-(2-(pyridin-3-yl)phenylmethyl)piperidin-1-yl)phenylcarbonyl,4-(4-(2-(2-methyl-4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2-methylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(methylsulfonyl)phenyl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfonylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor4-(4-((2-(4-methylsulfonylphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)-pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethyl-pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy, (1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino; D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN,NO₂, F, Cl, CF₃, OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(5-methylthien-2-yl)phenylmethyl)piperazin-1 -yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)cyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-methylsulfanylphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)phenylmethyl)piperazin-1-yl)-phenylcarbonyl,4-(4-(2-(4-(2-(morpholin-1-yl)ethoxy)-phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(morpholin-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(naphth-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(naphth-2-yl)phenylmethyl)-piperazin-1-yl)phenylcarbonyl or4-(4-(2-(4-phenoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-imidazol-2-yl)methyl)piperazin-1 -yl)phenylcarbonyl,4-(4-((1-phenyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(2-((phenylmethyl)amino)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)-4-(2-(dimethylamino)ethoxy))piperidin-1-yl)phenylcarbonyl,4-((2-(phenyl)phenylmethyl)-4-methoxypiperidin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)-4-(2-(morpholin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(phenyl)phenyl)phenylmethyl)piperazin-1 -yl)phenylcarbonyl or4-(4-(2-(phenyl)phenylmethyl)-4-(2-(piperidin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy, (1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(phenyl)phenylmethyl)-4-(2-(pyrrolidin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl,4-(4-((2-(phenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-pyrazol-5-yl)methyl)piperazin-1 -yl)phenylcarbonyl,4-(4-(2-(piperidin-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(pyrid-3-yl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-2-(quinolin-3-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(quinolin-8-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(thien-2-yl)phenylmethyl)-4-methoxypiperazin-1-yl)phenylcarbonyl,4-(4-(2-(thien-2-yl)phenylmethyl)-piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-trifluoromethoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor4-(4-(2-(4-trifluoromethylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy,(1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(1,3-benzodioxol-5-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(benzofuran-2-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-bromocyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-bromocyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-(4-bromophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclohept-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(1-(2-(4-chlorophenyl)cyclohex-1-en-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclooct-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(1-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylmethyl,4-(4-(2-(4-chlorophenyl)naphth-3-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)pyridin-3-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(4-chlorophenyl)pyridin-4-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)pyridin-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylcycloprop-1-yl)piperazin-1-yl)phenylcarbonylor4-(4-(2-(4-chlorophenyl)phenylmethyl)cyclohex-1-en-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)-pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethyl-pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy,(1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(5-(2-(4-chlorophenyl)phenylmethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)-4-methoxypiperidin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)-piperazin-1-yl)-3,5-difluorophenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-2-fluorophenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-3-fluorophenylcarbonyl,2-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)pyridin-5-ylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylmethyl)piperidin-4-yl)phenylcarbonyl,5-(4-(2-(4-chlorophenyl)phenylmethyl)-piperazin-1-yl)pyridin-2-ylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbonyl,4-(4-(2-(cyclohex-1-ylamino)phenylmethyl)piperazin-1-yl)phenylcarbonyl4-(4-(2-cyclohex-1-ylphenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3-cyanophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2,4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3,4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2,4-difluorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-(1,3-dihydro-2H-isoindol-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(1,1-dimethylethoxycarbonylamino)phenyl)piperazin-1-yl)phenylcarbonyl,4-(2-(4-(2-(dimethylamino)ethoxy)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor 4-(4-(3-(dimethylamino)phenyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy,(1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(2-(4-(dimethylamino)phenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(dimethylamino)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-(dimethylamino)phenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)-3-fluorophenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-fluorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(2-(isopropylamino)phenylmethyl)-piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(isopropylsulfanyl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methoxyphenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3-methoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-methoxyphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-methoxy-4-(2-(pyridin-3-yl)phenylmethyl)piperidin-1-yl)phenylcarbonyl,4-(4-(2-(2-methyl-4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2-methylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(methylsulfonyl)-phenyl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfonylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor4-(4-((2-(4-methylsulfonylphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy,(1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(5-methylthien-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)cyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-methylsulfanylphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)phenylmethyl)piperazin-1-yl)-phenylcarbonyl,4-(4-(2-(4-(2-(morpholin-1-yl)ethoxy)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(morpholin-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(naphth-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(naphth-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl or4-(4-(2-(4-phenoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(2-((phenylmethyl)amino)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)-4-(2-(dimethylamino)ethoxy))piperidin-1-yl)phenylcarbonyl,4-((2-(phenyl)phenylmethyl)-4-methoxypiperidin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)-4-(2-(morpholin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(phenyl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl or4-(4-(2-(phenyl)phenylmethyl)-4-(2-(piperidin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2,2-difluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethylamino,(1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethylamino,(3R)-5-(N-((dimethylamino)methylcarbonyl)amino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propoxy,(1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((pyrimidin-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-3-oxo-1-((1,3-thiazol-2-yl)methyl)propylamino,(1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((1,1-dimethylethoxy)carbonylamino)-1-((phenylsulfanyl)methyl)pentylamino,1-(1,1-dimethylethoxycarbonyl)piperidin-4-yloxy,1,1-dimethyl-2-(phenylsulfonyl)ethylamino,(1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino,1,1-dimethyl-2-(phenylsulfanyl)ethyl, 4,4-dimethylpiperidin-1-yl,(1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethylamino,(1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)-propylamino,1,1-dimethyl-2-(thien-2-ylsulfanyl)ethylamino,(1R)-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,1-(ethoxycarbonyl)piperidin-4-yloxy,(1R)73-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(phenyl)phenylmethyl)-4-(2-(pyrrolidin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl,4-(4-((2-(phenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(piperidin-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(pyrid-3-yl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(quinolin-3-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(quinolin-8-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(thien-2-yl)phenylmethyl)-4-methoxypiperazin-1-yl)phenylcarbonyl,4-(4-(2-(thien-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-trifluoromethoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor4-(4-(2-(4-trifluoromethylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-(4-(hydroxyaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2-hydroxy-2-methylpropyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4-hydroxypiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(3-hydroxypyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,isopropylamino,(1R)-3-(isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)-propylamino,(4-methoxycyclohex-1-yl)methyl)amino,(1R)-3-(4-(methoxyimino)piperidin-1-yl)-1-((phenylsulfanyl)methyl)-propylamino,(1R)-3-(N-methyl-N-carboxymethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(methyl)(cyclohexyl)amino, (methyl)(cyclohexylmethyl)amino,(1R)-3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(N-methyl-N-(dimethylcarbonylmethyl))-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(1,2-diphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-((diphenylmethyl)amino)carbonyl)-N-methylamino,(2-methylfuran-3-yl)sulfanyl)(1,1-spirobutyl)ethylamino,(1R)-3-(N-methyl-N-(2-hydroxyethyl))amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(4-methoxyphenyl)amino)carbonyl)-N-methylamino,1-methyl-4-(phenylsulfanyl)pyrrolidin-3-ylamino,(N-methyl-N-(4-methylphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(2-methylphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1-methylpiperidin-4-yloxy,(N-methyl-N-((S)-1-phenylethyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(4-methylpiperazin-4-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(morpholin-1-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(N,N-dimethylamino)amino)carbonyl)-N-methylamino,(1R)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1S)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1R)-4-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-(methyl(pyridin-4-yl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((methylsulfonylamino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(4-(methylsulfonylaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)-propylamino,2-((4-methyl-1,3-thiazol-2-yl)sulfanyl)ethylamino,(N-methyl-N-(4-trifluoromethoxyphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(morpholin-4-ylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2-(morpholin-4-yl)ethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-3-oxo-1-((2-thienylsulfanyl)methyl)-propylamino,(1R)-3-(morpholin-4-yl)-1-((1,3-thiazol-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methyl)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfonyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(1,3-benzodioxol-5-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(benzofuran-2-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-bromocyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-bromocyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-(4-bromophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclohept-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(1-(2-(4-chlorophenyl)cyclohex-1-en-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclooct-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(1-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylmethyl,4-(4-(2-(4-chlorophenyl)naphth-3-ylmethyl)piperazin-1-yl)-phenylcarbonyl,4-(4-(2-(4-chlorophenyl)pyridin-3-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(4-chlorophenyl)pyridin-4-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)pyridin-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylcycloprop-1-yl)piperazin-1-yl)phenylcarbonylor4-(4-(2-(4-chlorophenyl)phenylmethyl)cyclohex-1-en-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-(4-(hydroxyaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2-hydroxy-2-methylpropyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4-hydroxypiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(3-hydroxypyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,isopropylamino,(1R)-3-(isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)-propylamino,(4-methoxycyclohex-1-yl)methyl)amino,(1R)-3-(4-(methoxyimino)piperidin-1-yl)-1-((phenylsulfanyl)methyl)-propylamino,(1R)-3-(N-methyl-N-carboxymethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(methyl)(cyclohexyl)amino,(methyl)(cyclohexylmethyl)amino,(1R)-3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(N-methyl-N-(dimethylcarbonylmethyl))-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(1,2-diphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-((diphenylmethyl)amino)carbonyl)-N-methylamino,(2-methylfuran-3-yl)sulfanyl)-(1,1-spirobutyl)ethylamino,(1R)-3-(N-methyl-N-(2-hydroxyethyl))amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(4-methoxyphenyl)amino)carbonyl)-N-methylamino,1-methyl-4-(phenylsulfanyl)pyrrolidin-3-ylamino,(N-methyl-N-(4-methylphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(2-methylphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1-methylpiperidin-4-yloxy,(N-methyl-N-((S)-1-phenylethyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(4-methylpiperazin-4-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(morpholin-1-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(N,N-dimethylamino))amino)carbonyl)-N-methylamino,(1R)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1S)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1R)-4-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-(methyl(pyridin-4-yl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((methylsulfonylamino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(4-(methylsulfonylaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)-propylamino,2-((4-methyl-1,3-thiazol-2-yl)sulfanyl)ethylamino,(N-methyl-N-(4-trifluoromethoxyphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(morpholin-4-ylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2-(morpholin-4-yl)ethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-3-oxo-1-((2-thienylsulfanyl)methyl)-propylamino,(1R)-3-(morpholin-4-yl)-1-((1,3-thiazol-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methyl)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfonyl)-methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(5-(2-(4-chlorophenyl)phenylmethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)-piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)-4-methoxypiperidin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-3,5-difluorophenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-2-fluorophenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-3-fluorophenylcarbonyl,2-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)pyridin-5-ylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylmethyl)piperidin-4-yl)phenylcarbonyl,5-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)pyridin-2-ylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbonyl,4-(4-(2-(cyclohex-1-ylamino)phenylmethyl)piperazin-1-yl)phenylcarbonyl4-(4-(2-cyclohex-1-ylphenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3-cyanophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2,4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3,4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2,4-difluorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-(1,3-dihydro-2H-isoindol-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(1,1-dimethylethoxycarbonylamino)phenyl)piperazin-1-yl)phenylcarbonyl,4-(2-(4-(2-(dimethylamino)ethoxy)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor 4-(4-(3-(dimethylamino)phenyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-(4-(hydroxyaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2-hydroxy-2-methylpropyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4-hydroxypiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(3-hydroxypyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,isopropylamino,(1R)-3-(isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(4-methoxycyclohex-1-yl)methyl)amino,(1R)-3-(4-(methoxyimino)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-carboxymethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(methyl)(cyclohexyl)amino, (methyl)(cyclohexylmethyl)amino,(1R)-3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(N-methyl-N-(dimethylcarbonylmethyl))-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(1,2-diphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-((diphenylmethyl)amino)carbonyl)-N-methylamino,(2-methylfuran-3-yl)sulfanyl)-(1,1-spirobutyl)ethylamino,(1R)-3-(N-methyl-N-(2-hydroxyethyl))amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(4-methoxyphenyl)amino)carbonyl)-N-methylamino,1-methyl-4-(phenylsulfanyl)pyrrolidin-3-ylamino,(N-methyl-N-(4-methylphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(2-methylphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1-methylpiperidin-4-yloxy,(N-methyl-N-((S)-1-phenylethyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(4-methylpiperazin-4-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(morpholin-1-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(N,N-dimethylamino))amino)carbonyl)-N-methylamino,(1R)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1S)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1R)-4-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-(methyl(pyridin-4-yl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((methylsulfonylamino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(4-(methylsulfonylaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,2-((4-methyl-1,3-thiazol-2-yl)sulfanyl)ethylamino,(N-methyl-N-(4-trifluoromethoxyphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(morpholin-4-ylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2-(morpholin-4-yl)ethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-3-oxo-1-((2-thienylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((1,3-thiazol-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methyl)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfonyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(2-(4-(dimethylamino)phenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(dimethylamino)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-(dimethylamino)phenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)phenylmethyl)-piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)-3-fluorophenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-fluorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(2-(isopropylamino)phenylmethyl)-piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(isopropylsulfanyl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methoxyphenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3-methoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-methoxyphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-methoxy-4-(2-(pyridin-3-yl)phenylmethyl)piperidin-1-yl)phenylcarbonyl,4-(4-(2-(2-methyl-4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2-methylphenyl)phenylmethyl)-piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(methylsulfonyl)-phenyl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfonylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor4-(4-((2-(4-methylsulfonylphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-(4-(hydroxyaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2-hydroxy-2-methylpropyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4-hydroxypiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(3-hydroxypyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,isopropylamino,(1R)-3-(isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(4-methoxycyclohex-1-yl)methyl)amino,(1R)-3-(4-(methoxyimino)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-carboxymethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(methyl)(cyclohexyl)amino, (methyl)(cyclohexylmethyl)amino,(1R)-3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(N-methyl-N-(dimethylcarbonylmethyl))-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(1,2-diphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-((diphenylmethyl)amino)carbonyl)-N-methylamino,(2-methylfuran-3-yl)sulfanyl)-(1,1-spirobutyl)ethylamino,(1R)-3-(N-methyl-N-(2-hydroxyethyl))amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(4-methoxyphenyl)amino)carbonyl)-N-methylamino,1-methyl-4-(phenylsulfanyl)pyrrolidin-3-ylamino,(N-methyl-N-(4-methylphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(2-methylphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1-methylpiperidin-4-yloxy,(N-methyl-N-((S)-1-phenylethyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(4-methylpiperazin-4-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(morpholin-1-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(N,N-dimethylamino))amino)carbonyl)-N-methylamino,(1R)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1S)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1R)-4-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-(methyl(pyridin-4-yl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((methylsulfonylamino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(4-(methylsulfonylaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,2-((4-methyl-1,3-thiazol-2-yl)sulfanyl)ethylamino,(N-methyl-N-(4-trifluoromethoxyphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(morpholin-4-ylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2-(morpholin-4-yl)ethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-3-oxo-1-((2-thienylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((1,3-thiazol-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methyl)phenyl)sulfanyl)methylpropylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfonyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(5-methylthien-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)cyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-methylsulfanylphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(2-(morpholin-1-yl)ethoxy)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(morpholin-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(naphth-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(naphth-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl or4-(4-(2-(4-phenoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(2-((phenylmethyl)amino)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)-4-(2-(dimethylamino)ethoxy))piperidin-1-yl)phenylcarbonyl,4-((2-(phenyl)phenylmethyl)-4-methoxypiperidin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)-4-(2-(morpholin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(phenyl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl or4-(4-(2-(phenyl)phenylmethyl)-4-(2-(piperidin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-(4-(hydroxyaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(2-hydroxy-2-methylpropyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(4-hydroxypiperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(3-hydroxypyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,isopropylamino,(1R)-3-(isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)-propylamino,(4-methoxycyclohex-1-yl)methyl)amino,(1R)-3-(4-(methoxyimino)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-carboxymethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(methyl)(cyclohexyl)amino, (methyl)(cyclohexylmethyl)amino,(1R)-3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(3R)-3-(N-methyl-N-(dimethylcarbonylmethyl))-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(1,2-diphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-((diphenylmethyl)amino)carbonyl)-N-methylamino,(2-methylfuran-3-yl)sulfanyl)-(1,1-spirobutyl)ethylamino,(1R)-3-(N-methyl-N-(2-hydroxyethyl))amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(N-methyl-N-isopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(N-methyl-N-(4-methoxyphenyl)amino)carbonyl)-N-methylamino,1-methyl-4-(phenylsulfanyl)pyrrolidin-3-ylamino,(N-methyl-N-(4-methylphenyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(2-methylphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,1-methylpiperidin-4-yloxy,(N-methyl-N-((S)-1-phenylethyl)amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(4-methylpiperazin-4-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(morpholin-1-yl))amino)carbonyl)-N-methylamino,(N-methyl-N-(1-phenyl-2-(N,N-dimethylamino))amino)carbonyl)-N-methylamino,(1R)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1S)-1-methyl-2-((phenylsulfanyl)methyl)ethylamino,(1R)-4-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)butylamino,(1R)-3-(methyl(pyridin-4-yl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-5-((methylsulfonylamino)-1-((phenylsulfanyl)methyl)pentylamino,(1R)-3-(4-(methylsulfonylaminocarbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,2-((4-methyl-1,3-thiazol-2-yl)sulfanyl)ethylamino,(N-methyl-N-(4-trifluoromethoxyphenyl)amino)carbonyl)-N-methylamino,(1R)-3-(morpholin-4-ylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((2-(morpholin-4-yl)ethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-3-oxo-1-((2-thienylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((1,3-thiazol-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((thien-2-ylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methoxy)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(methyl)phenyl)sulfanyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-((phenylsulfonyl)methyl)propylamino,(1R)-3-(morpholin-4-yl)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propylamino;D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂ or C(O)NH₂; and Z¹ is4-(4-(2-(phenyl)phenylmethyl)-4-(2-(pyrrolidin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl,4-(4-((2-(phenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(piperidin-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(pyrid-3-yl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(quinolin-3-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(quinolin-8-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(thien-2-yl)phenylmethyl)-4-methoxypiperazin-1-yl)phenylcarbonyl,4-(4-(2-(thien-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-trifluoromethoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor4-(4-(2-(4-trifluoromethyl-phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclobutylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfonylmethyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((pyrimidin-1-ylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-((1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)-propylamino,(1R)-3-oxo-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-amino-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(methylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(morpholin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(2-(morpholin-1-yl)ethyl)-1-((phenylsulfanyl)methyl)propylamino,(2-phenoxyethyl)amino, 4-(1-(phenylmethyl)piperidin-4-yl)amino,4-(1-(phenylmethyl)piperidin-4-yl)methylamino,(4-phenyl-1,3-thiazol-2-ylsulfanyl)ethylamino,(1R,2S)-2-(phenylsulfanyl)cyclohex-1-ylamino,(1S,2R)-2-(phenylsulfanyl)cyclohex-1-ylamino,2-(phenylsulfanyl)cyclopentylamino, 2-(phenylsulfanyl)ethoxy,2-(phenylsulfanyl)ethylamino, 2-(phenylsulfonyl)ethylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(morpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propylamino,4-(phenylsulfonyl)tetrahydrofuran-3-ylamino,4-(phenylsulfanyl)tetrahydrofuran-3-ylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propylamino,(1S)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-4-ylsulfanyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(thiomorpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(piperazin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2-(pyridin-2-yl)ethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-4-ylmethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-3-ylamino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-ylamino)propylamino),(1R)-1-((phenylsulfanyl)methyl)-3-(2H-tetrazol-5-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)3-((pyridin-2-ylmethyl)amino)propylamino,(1S)-2-(phenylsulfanyl)-1-(pyridin-3-ylmethyl)ethylamino,(3S,4R)-(phenylsulfanyl)pyrrolidin-4-ylamino,2-(phenylsulfanyl)-1,1-spirobutylethylamino,2-(phenylsulfanyl)-1,1-spiroethylethylamino,2-(phenylsulfanyl)-1,1-spiropentylethylamino, piperidin-4-yloxy,(1-propylpiperidin-4-yl)methylamino, pyran-4-ylamino,2-(pyridin-4-ylsulfanyl)ethylamino,2-(pyrimidin-2-ylsulfanyl)ethylamino,1,1-spirobutyl-2-(phenylsulfanyl)ethyl,2-(thien-2-ylsulfanyl)ethylamino, sulfanylpyran-4-ylamino,(1R)-3-(2-(2H-tetrazol-3-yl)pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(3-(2H-tetrazol-3-yl)azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylaminoor 2-(1,3-thiazol-2-ylsulfanyl)ethylamino; D¹ is H, F, Cl or CF₃; E¹ isH, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃, OCF₃, NH₂ or C(O)NH₂; and Z¹ Zis4-(4-(2-(1,3-benzodioxol-5-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(benzofuran-2-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-bromocyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-bromocyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-(4-bromophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclohept-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(1-(2-(4-chlorophenyl)cyclohex-1-en-1-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclohex-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)cyclooct-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(1-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylmethyl,4-(4-(2-(4-chlorophenyl)naphth-3-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)pyridin-3-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(4-chlorophenyl)pyridin-4-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((4-(4-chlorophenyl)pyridin-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylcycloprop-1-yl)piperazin-1-yl)phenylcarbonylor4-(4-(2-(4-chlorophenyl)phenylmethyl)cyclohex-1-en-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclobutylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfonylmethyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((pyrimidin-1-ylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-((1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)-propylamino,(1R)-3-oxo-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-amino-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(methylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)-propylamino,(1R)-3-oxo-3-(morpholin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(2-(morpholin-1-yl)ethyl)-1-((phenylsulfanyl)methyl)propylamino,(2-phenoxyethyl)amino, 4-(1-(phenylmethyl)piperidin-4-yl)amino,4-(1-(phenylmethyl)piperidin-4-yl)methylamino,(4-phenyl-1,3-thiazol-2-ylsulfanyl)ethylamino,(1R,2S)-2-(phenylsulfanyl)cyclohex-1-ylamino,(1S,2R)-2-(phenylsulfanyl)cyclohex-1-ylamino,2-(phenylsulfanyl)cyclopentylamino, 2-(phenylsulfanyl)ethoxy,2-(phenylsulfanyl)ethylamino, 2-(phenylsulfonyl)ethylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(morpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propylamino,4-(phenylsulfonyl)tetrahydrofuran-3-ylamino,4-(phenylsulfanyl)tetrahydrofuran-3-ylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)-amino)propylamino,(1S)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-4-ylsulfanyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(thiomorpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(piperazin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2-(pyridin-2-yl)ethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-4-ylmethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-3-ylamino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-ylamino)propylamino),(1R)-1-((phenylsulfanyl)methyl)-3-(2H-tetrazol-5-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)3-((pyridin-2-ylmethyl)amino)propylamino,(1S)-2-(phenylsulfanyl)-1-(pyridin-3-ylmethyl)ethylamino,(3S,4R)-(phenylsulfanyl)pyrrolidin-4-ylamino,2-(phenylsulfanyl)-1,1-spirobutylethylamino,2-(phenylsulfanyl)-1,1-spiroethylethylamino,2-(phenylsulfanyl)-1,1-spiropentylethylamino, piperidin-4-yloxy,(1-propylpiperidin-4-yl)methylamino, pyran-4-ylamino,2-(pyridin-4-ylsulfanyl)ethylamino,2-(pyrimidin-2-ylsulfanyl)ethylamino,1,1-spirobutyl-2-(phenylsulfanyl)ethyl,2-(thien-2-ylsulfanyl)ethylamino, sulfanylpyran-4-ylamino,(1R)-3-(2-(2H-tetrazol-3-yl)pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(3-(2H-tetrazol-3-yl)azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylaminoor 2-(1,3-thiazol-2-ylsulfanyl)ethylamino; D¹ is H, F, Cl or CF₃; E¹ isH, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃, OCF₃, NH₂ or C(O)NH₂; and Z¹is4-(5-(2-(4-chlorophenyl)phenylmethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)-4-methoxypiperidin-1-yl)phenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)-piperazin-1-yl)-3,5-difluorophenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-2-fluorophenylcarbonyl,4-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)-3-fluorophenylcarbonyl,2-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)pyridin-5-ylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylmethyl)piperidin-4-yl)phenylcarbonyl,5-(4-(2-(4-chlorophenyl)phenylmethyl)piperazin-1-yl)pyridin-2-ylcarbonyl,4-(1-(2-(4-chlorophenyl)phenylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbonyl,4-(4-(2-(cyclohex-1-ylamino)phenylmethyl)piperazin-1-yl)phenylcarbonyl4-(4-(2-cyclohex-1-ylphenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3-cyanophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2,4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3,4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2,4-difluorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(2-(1,3-dihydro-2H-isoindol-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(1,1-dimethylethoxycarbonylamino)phenyl)piperazin-1-yl)phenylcarbonyl,4-(2-(4-(2-(dimethylamino)ethoxy)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor 4-(4-(3-(dimethylamino)phenyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)-propylamino,(1R)-3-oxo-3-(azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclobutylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfonylmethyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((pyrimidin-1-ylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-((1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)-propylamino,(1R)-3-oxo-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-amino-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(methylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(morpholin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(2-(morpholin-1-yl)ethyl)-1-((phenylsulfanyl)methyl)propylamino,(2-phenoxyethyl)amino, 4-(1-(phenylmethyl)piperidin-4-yl)amino,4-(1-(phenylmethyl)piperidin-4-yl)methylamino,(4-phenyl-1,3-thiazol-2-ylsulfanyl)ethylamino,(1R,2S)-2-(phenylsulfanyl)cyclohex-1-ylamino,(1S,2R)-2-(phenylsulfanyl)cyclohex-1-ylamino,2-(phenylsulfanyl)cyclopentylamino, 2-(phenylsulfanyl)ethoxy,2-(phenylsulfanyl)ethylamino, 2-(phenylsulfonyl)ethylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(morpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propylamino,4-(phenylsulfonyl)tetrahydrofuran-3-ylamino,4-(phenylsulfanyl)tetrahydrofuran-3-ylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propylamino,(1S)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-4-ylsulfanyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(thiomorpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(piperazin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2-(pyridin-2-yl)ethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-4-ylmethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-3-ylamino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-ylamino)propylamino),(1R)-1-((phenylsulfanyl)methyl)-3-(2H-tetrazol-5-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-2-ylmethyl)amino)propylamino,(1S)-2-(phenylsulfanyl)-1-(pyridin-3-ylmethyl)ethylamino,(3S,4R)-(phenylsulfanyl)pyrrolidin-4-ylamino,2-(phenylsulfanyl)-1,1-spirobutylethylamino,2-(phenylsulfanyl)-1,1-spiroethylethylamino,2-(phenylsulfanyl)-1,1-spiropentylethylamino, piperidin-4-yloxy,(1-propylpiperidin-4-yl)methylamino, pyran-4-ylamino,2-(pyridin-4-ylsulfanyl)ethylamino,2-(pyrimidin-2-ylsulfanyl)ethylamino,1,1-spirobutyl-2-(phenylsulfanyl)ethyl,2-(thien-2-ylsulfanyl)ethylamino, sulfanylpyran-4-ylamino,(1R)-3-(2-(2H-tetrazol-3-yl)pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(3-(2H-tetrazol-3-yl)azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylaminoor 2-(1,3-thiazol-2-ylsulfanyl)ethylamino; D¹ is H, F, Cl or CF₃; E¹ isH, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃, OCF₃, NH₂ or C(O)NH₂; and Z¹is4-(2-(4-(dimethylamino)phenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(dimethylamino)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-(dimethylamino)phenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)-3-fluorophenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-fluorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-fluorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(2-(isopropylamino)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(isopropylsulfanyl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methoxyphenyl)cyclopent-1-en-1-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(3-methoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-methoxyphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-methoxy-4-(2-(pyridin-3-yl)phenylmethyl)piperidin-1-yl)phenylcarbonyl,4-(4-(2-(2-methyl-4-dichlorophenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(2-methylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(methylsulfonyl)phenyl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfonylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor4-(4-((2-(4-methylsulfonylphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclobutylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfonylmethyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((pyrimidin-1-ylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-((1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-amino-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(methylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(morpholin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(2-(morpholin-1-yl)ethyl)-1-((phenylsulfanyl)methyl)propylamino,(2-phenoxyethyl)amino, 4-(1-(phenylmethyl)piperidin-4-yl)amino,4-(1-(phenylmethyl)piperidin-4-yl)methylamino,(4-phenyl-1,3-thiazol-2-ylsulfanyl)ethylamino,(1R,2S)-2-(phenylsulfanyl)cyclohex-1-ylamino,(1S,2R)-2-(phenylsulfanyl)cyclohex-1-ylamino,2-(phenylsulfanyl)cyclopentylamino, 2-(phenylsulfanyl)ethoxy,2-(phenylsulfanyl)ethylamino, 2-(phenylsulfonyl)ethylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(morpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propylamino,4-(phenylsulfonyl)tetrahydrofuran-3-ylamino,4-(phenylsulfanyl)tetrahydrofuran-3-ylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)-amino)propylamino,(1S)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-4-ylsulfanyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(thiomorpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(piperazin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2-(pyridin-2-yl)ethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-4-ylmethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-3-ylamino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-ylamino)propylamino),(1R)-1-((phenylsulfanyl)methyl)-3-(2H-tetrazol-5-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-2-ylmethyl)amino)propylamino,(1S)-2-(phenylsulfanyl)-1-(pyridin-3-ylmethyl)ethylamino,(3S,4R)-(phenylsulfanyl)pyrrolidin-4-ylamino,2-(phenylsulfanyl)-1,1-spirobutylethylamino,2-(phenylsulfanyl)-1,1-spiroethylethylamino,2-(phenylsulfanyl)-1,1-spiropentylethylamino, piperidin-4-yloxy,(1-propyl-piperidin-4-yl)methylamino, pyran-4-ylamino,2-(pyridin-4-ylsulfanyl)ethylamino,2-(pyrimidin-2-ylsulfanyl)ethylamino,1,1-spirobutyl-2-(phenylsulfanyl)ethyl,2-(thien-2-ylsulfanyl)ethylamino, sulfanylpyran-4-ylamino,(1R)-3-(2-(2H-tetrazol-3-yl)pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(3-(2H-tetrazol-3-yl)azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylaminoor 2-(1,3-thiazol-2-ylsulfanyl)ethylamino; D¹ is H, F, Cl or CF₃; E¹ isH, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃, OCF₃, NH₂ or C(O)NH₂; and Z¹is4-(4-(2-(5-methylthien-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)cyclohex-1-en-l-ylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)phenylcarbonyl)piperazin-1-yl)phenylcarbonyl,4-(4-((2-(4-methylsulfanylphenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-methylsulfanylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(2-(morpholin-1-yl)ethoxy)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(morpholin-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(naphth-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(naphth-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl4-(4-(2-(4-phenoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(2-((phenylmethyl)amino)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)-4-(2-(dimethylamino)ethoxy))piperidin-1-yl)phenylcarbonyl,4-((2-(phenyl)phenylmethyl)-4-methoxypiperidin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)-4-(2-(morpholin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl,4-(4-(2-(phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(3-(phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-(phenyl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl or4-(4-(2-(phenyl)phenylmethyl)-4-(2-(piperidin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I), ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)OCH₃ or C(O)NH₂; B¹ is(1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclobutylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(cyclopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((phenylsulfonylmethyl)methyl)propylamino,(1R)-3-oxo-3-(dimethylamino)-1-((pyrimidin-1-ylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-((1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(1,1-dioxothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(N-methyl-N-(1,1-dimethylethyl)amino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(piperidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-amino-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(methylamino)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(morpholin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-oxo-3-(2-(morpholin-1-yl)ethyl)-1-((phenylsulfanyl)methyl)propylamino,(2-phenoxyethyl)amino, 4-(1-(phenylmethyl)piperidin-4-yl)amino,4-(1-(phenylmethyl)piperidin-4-yl)methylamino,(4-phenyl-1,3-thiazol-2-ylsulfanyl)ethylamino,(1R,2S)-2-(phenylsulfanyl)cyclohex-1-ylamino,(1S,2R)-2-(phenylsulfanyl)cyclohex-1-ylamino,2-(phenylsulfanyl)cyclopentylamino, 2-(phenylsulfanyl)ethoxy,2-(phenylsulfanyl)ethylamino, 2-(phenylsulfonyl)ethylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(morpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propylamino,4-(phenylsulfonyl)tetrahydrofuran-3-ylamino,4-(phenylsulfanyl)tetrahydrofuran-3-ylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propylamino,(1S)-1-((phenylsulfanyl)methyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-4-ylsulfanyl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(thiomorpholin-4-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(piperazin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((2-(pyridin-2-yl)ethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-4-ylmethyl)amino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-3-ylamino)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-ylamino)propylamino),(1R)-1-((phenylsulfanyl)methyl)-3-(2H-tetrazol-5-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propylamino,(1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-2-ylmethyl)amino)propylamino,(1S)-2-(phenylsulfanyl)-1-(pyridin-3-ylmethyl)ethylamino,(3S,4R)-(phenylsulfanyl)pyrrolidin-4-ylamino,2-(phenylsulfanyl)-1,1-spirobutylethylamino,2-(phenylsulfanyl)-1,1-spiroethylethylamino,2-(phenylsulfanyl)-1,1-spiropentylethylamino, piperidin-4-yloxy,(1-propylpiperidin-4-yl)methylamino, pyran-4-ylamino,2-(pyridin-4-ylsulfanyl)ethylamino,2-(pyrimidin-2-ylsulfanyl)ethylamino,1,1-spirobutyl-2-(phenylsulfanyl)ethyl,2-(thien-2-ylsulfanyl)ethylamino, sulfanylpyran-4-ylamino,(1R)-3-(2-(2H-tetrazol-3-yl)pyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propylamino,(1R)-3-(3-(2H-tetrazol-3-yl)azetidin-1-yl)-1-((phenylsulfanyl)methyl)propylaminoor 2-(1,3-thiazol-2-ylsulfanyl)ethylamino; D¹ is H, F, Cl or CF₃; E¹ isH, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃, OCF₃, NH₂ or C(O)NH₂ and Z¹ is4-(4-(2-(phenyl)phenylmethyl)-4-(2-(pyrrolidin-1-yl)ethoxy))piperidin-1-yl)phenylcarbonyl,4-(4-((2-(phenyl)pyridin-3-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-((1-phenyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(piperidin-1-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(pyrid-3-yl)phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(quinolin-3-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(quinolin-8-ylphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(thien-2-yl)phenylmethyl)-4-methoxypiperazin-1-yl)phenylcarbonyl,4-(4-(2-(thien-2-yl)phenylmethyl)piperazin-1-yl)phenylcarbonyl,4-(4-(2-(4-trifluoromethoxyphenyl)phenylmethyl)piperazin-1-yl)phenylcarbonylor4-(4-(2-(4-trifluoromethyl-phenyl)phenylmethyl)piperazin-1-yl)phenylcarbonyl.

Still another embodiment pertains to compounds having formula (I) whichare

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(MR)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(MR)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-methoxy(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-fluoro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-(methylsulfanyl)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(4′-phenyl-1,1′-biphenyl-2-ylmethyl)piperazin-1-yl)benzamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((4′-phenoxy(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethylamino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-4-(dimethylamino)-1-((phenylsulfanyl)methyl)butyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylsulfanyl)methyl)pentyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-fluoro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro-4-fluoro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(1,3-thiazol-2-ylsulfanyl)ethylamino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((1,3-thiazol-2-ylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((thien-2-ylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-2-(2-(dimethylamino)ethoxy)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1S)-3-(dimethylamino)-1-methyl-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(methylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butanoicacid,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N-isopropyl-4-(phenylsulfanyl)butanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(azetidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((4-(phenylsulfanyl)tetrahydro-3-furanyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)-4-methoxypiperidin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)-4-methoxypiperidin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-hydroxy-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(isopropylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(2-naphthyl)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(1-naphthyl)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((3′-cyano(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((3′-methoxy(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((3′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide

N-(4-(4-((2′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-(2-(1,3-benzodioxol-5-yl)benzyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-(2-(3-thienyl)benzyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-(2-(pyridin-3-yl)benzyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-(2-(quinolin-8-yl)benzyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

N-(4-(4-(2-(1-benzofuran-2-yl)benzyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2′-methyl(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-(2-(quinolin-3-yl)benzyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

N-(4-(4-((1-(4-chlorophenyl)-2-naphthyl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1-(4-chlorophenyl)-2-naphthyl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1-(4-chlorophenyl)-2-naphthyl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)cyclopentyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)cyclopentyl)amino)benzenesulfonamide,

N-(4-(4-((4′-fluoro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethylamino)benzenesulfonamide,

N-(4-(4-((3′,4′-dichloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((3′,4′-dichloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((3′,4′-dichloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)-N-(4-(4-((4′-(trifluoromethyl)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((4′-(trifluoromethyl)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((4′-(trifluoromethyl)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)-N-(4-(4-((4′-(trifluoromethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)-N-(4-(4-((4′-(trifluoromethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((4′-(trifluoromethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

3-nitro-N-(4-(4-((4′-phenoxy(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((4′-phenoxy(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfonyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2′,4′-dichloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-(2-(2-thienyl)benzyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

N-(4-(4-((4′-chloro-2′-methyl(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2′,4′-difluoro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfonyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfonyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((4-(phenylsulfanyl)tetrahydro-3-furanyl)amino)benzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(5-methyl-2-thienyl)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((4-(phenylsulfonyl)tetrahydro-3-furanyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((4-(phenylsulfonyl)tetrahydro-3-furanyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((1-methyl-4-(phenylsulfanyl)pyrrolidin-3-yl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-bromo(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-(1-(4′-chloro(1,1′-biphenyl)-2-yl)cyclopropyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-2-(dimethylamino)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-2-(dimethylamino)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-2-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-2-(diethylamino)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-2-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(cyclopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-methoxy-4-(2-(pyridin-3-yl)benzyl)piperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-methoxy-4-(2-(pyridin-4-yl)benzyl)piperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-methoxy-4-(2-(2-thienyl)benzyl)piperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-methoxy-4-(2-(3-thienyl)benzyl)piperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(azetidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-((2,2,2-trifluoroethyl)amino)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(methyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)-4-methoxypiperidin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(ethyl(2,2,2-trifluoroethyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2-fluoroethyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2,2-difluoroethyl)amino)-1-amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-1-((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)-1H-benzimidazole-5-sulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-1-((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)-1H-1,2,3-benzotriazole-5-sulfonamide,

5-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)benzamide,

N-(4-(4-((4′-(dimethylamino)(1,1′-biphenyl)-2-yl)carbonyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-(methylsulfanyl)(1,1′-biphenyl)-2-yl)carbonyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-(methylsulfanyl)(1,1′-biphenyl)-2-yl)carbonyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-cyano-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)oxy)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(5,6-dihydro-1(4H)-pyrimidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(2,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(4,4-dimethyl-4,5-dihydro-1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)oxy)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

4-(((1R)-3-(bis(2-methoxyethyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(bis(2-methoxyethyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-(trifluoromethyl)benzenesulfonamide,

4-(((1R)-5-amino-1-((phenylsulfanyl)methyl)pentyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-4-yl)methyl)-1-piperazinyl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1R)-4-methyl-1-((phenylsulfanyl)methyl)pentyl)amino)-3-nitrobenzenesulfonamide,

tert-butyl(5R)-5-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-6-(phenylsulfanyl)hexylcarbamate,

4-(((1R)-5-amino-1-((phenylsulfanyl)methyl)pentyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-5-((methylsulfonyl)amino)-1-((phenylsulfanyl)methyl)pentyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-5-((aminocarbonyl)amino)-1-((phenylsulfanyl)methyl)pentyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(methylsulfanyl)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(methylsulfonyl)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-(2-cyclohexylbenzyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(morpholin-4-yl)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(isopropylsulfanyl)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dipropylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-3-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-3-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-3-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)-3-fluorobenzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)-3-fluorobenzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)-3-fluorobenzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)-3,5-difluorobenzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)-3,5-difluorobenzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)-3,5-difluorobenzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

3-nitro-N-(4-(4-((1-phenyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((1-phenyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

3-nitro-N-(4-(4-((1-phenyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzoyl)-4-((2-(phenylsulfanyl)ethylamino)benzenesulfonamide,

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((1-phenyl-1H-pyrazol-5′-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((1-phenyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((1-phenyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

1-((3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butyl)-3-azetidinecarboxylicacid,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2-hydroxy-2-methylpropyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

(((3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butyl)(methyl)amino)aceticacid,

(2R)-1-((3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butyl)-2-pyrrolidinecarboxylicacid

1-((3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butyl)-4-piperidinecarboxylicacid

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2-hydroxyethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

(2S)-1-((3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butyl)-2-pyrrolidinecarboxylicacid,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(3-(2H-tetrazol-5-yl)azetidin-1-yl)propyl)amino)benzenesulfonamide,

(2S)-2-amino-N-((1S)-2-(((3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butyl)amino)-1-methyl-2-oxoethyl)propanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(2-(2H-tetrazol-5-yl)pyrrolidin-1-yl)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(4-(((methylsulfonyl)amino)carbonyl)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

1-((3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butyl)-N-hydroxy-4-piperidinecarboxamide,

2-chloro-N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

2,6-dichloro-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

4-(((1R)-3-((1R,5S)-8-azabicyclo[3.2.1]oct-8-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(7-azabicyclo[2.2.1]hept-7-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(2-(phenylsulfanyl)ethoxy)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(2-(phenylsulfanyl)ethoxy)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

4-(((1R)-3-(7-azabicyclo[2.2.1]hept-7-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(cyclohexyloxy)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(cyclohexylmethoxy)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(2-cyclohexylethoxy)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((2-cyclohexylethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(cyclohexyl(methyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(4,4-dimethylpiperidin-1-yl)-3-nitrobenzenesulfonamide,

tert-butyl4-(4-(((4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitrophenoxy)-1-piperidinecarboxylate,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-(piperidin-4-yloxy)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((1-methylpiperidin-4-yl)oxy)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((cyclohexylmethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((cyclohexylmethyl)(propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1-benzylpiperidin-4-yl)methyl)amino)-N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((cyclohexylmethyl)(methyl)amino)-3-nitrobenzenesulfonamide,

4-((1-benzylpiperidin-4-yl)amino)-N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-(tetrahydro-2H-sulfanylpyran-4-ylamino)benzenesulfonamide,

ethyl4-(4-(((4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-1-piperidinecarboxylate,

N-(4-(4-((1,1-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1-propylpiperidin-4-yl)methyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(isopropylamino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(1,3-thiazol-2-ylsulfanyl)ethylamino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-((4-phenyl-1,3-thiazol-2-yl)sulfanyl)ethylamino)benzenesulfonamide,

4-((2-(1,3-benzothiazol-2-ylsulfanyl)ethylamino)-N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(1,3-thiazol-2-ylsulfanyl)ethylamino)benzenesulfonamide,

4-((2-(1,3-benzoxazol-2-ylsulfanyl)ethyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-((2-(1,3-benzothiazol-2-ylsulfanyl)ethylamino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(pyrimidin-2-ylsulfanyl)ethyl)amino)benzenesulfonamide,

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((1-phenyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1-benzylpiperidin-4-yl)methyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((2-bromoethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((2-((4-methyl-1,3-thiazol-2-yl)sulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((4-methoxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(2-thienylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(2-thienylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((1,3-thiazol-2-ylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N,N-dimethyl-4-(pyrimidin-2-ylsulfanyl)butanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-3-oxo-1-((2-thienylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(pyrimidin-2-ylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N,N-dimethyl-4-(1,3-thiazol-2-ylsulfanyl)butanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((2-thienylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-phenoxyethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-(((4-(trifluoromethoxy)phenyl)sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1-(((4-methoxyphenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1-(((4-methylphenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((2-thienylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1-(((4-chlorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-(((4-fluorophenyl)sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1-(((4-fluorophenyl)sulfanyl)methyl)-3-(morpholin-4-yl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-2-fluorobenzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-2-fluorobenzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-((6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)carbonyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperidin-4-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperidin-4-yl)benzoyl)-4(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-((6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)carbonyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-((6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)carbonyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperidin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperidin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-((5-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)pyridin-2-yl)carbonyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-((5-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)pyridin-2-yl)carbonyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(1-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)-1-cyclohexen-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)-1-cyclohexen-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-((3aR,6aS)-5-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(methyl((methyl-4-(trifluoromethoxy)anilino)carbonyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((2-dimethylanilino)carbonyl)(methyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((4-methoxy(methyl)anilino)carbonyl)(methyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((4-dimethylanilino)carbonyl)(methyl)amino)-3-nitrobenzenesulfonamide,

4-(((benzhydryl(methyl)amino)carbonyl)(methyl)amino)-N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(methyl((methyl((1S)-1-phenylethyl)amino)carbonyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(methyl((methyl(2-(4-methylpiperazin-1-yl)-1-phenylethyl)amino)carbonyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(methyl((methyl(2-(morpholin-4-yl)-1-phenylethyl)amino)carbonyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((((1,2-diphenylethyl)(methyl)amino)carbonyl)(methyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((((2-(dimethylamino)-1-phenylethyl)(methyl)amino)carbonyl)(methyl)amino)-3-nitrobenzenesulfonamide,

3-amino-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-1-(2-(phenylsulfanyl)ethyl-1H-1,2,3-benzotriazole-5-sulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-1-(2-(phenylsulfanyl)ethyl)-1H-benzimidazole-5-sulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-4-((cyclohexylmethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-4-(cyclohexylamino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((1-((phenylsulfanyl)methyl)cyclopentyl)amino)benzene-sulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-((1-((phenylsulfanyl)methyl)cyclopentyl)amino)benzene-sulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((1-((phenylsulfanyl)methyl)cyclopentyl)amino)benzene-sulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1S)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-(((1S)-1-((phenylsulfanyl)methyl)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((15)-3-methyl-1-((phenylsulfanyl)methyl)butyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-4-(((1S)-3-methyl-1-((phenylsulfanyl)methyl)butyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((1-((phenylsulfanyl)methyl)cyclopropyl)amino)benzene-sulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((1-((phenylsulfanyl)methyl)cyclohexyl)amino)benzene-sulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1-methyl-2-(phenylsulfanyl)ethylamino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1S)-1-methyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R,2S)-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

4-(((1R)-5-amino-1-((phenylsulfanyl)methyl)pentyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1S)-2-(phenylsulfanyl)-1-(pyridin-3-ylmethyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-(((1S)-2-(phenylsulfanyl)-1-(pyridin-3-ylmethyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1S,2R)-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((1-(((2-methyl-3-furyl)sulfanyl)methyl)cyclopentyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((1-(((2-methyl-3-furyl)sulfanyl)methyl)cyclopentyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1S)-2-(phenylsulfanyl)-1-(pyridin-3-ylmethyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-3-pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

3-nitro-N-(4-(4-((2-phenylpyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((2-phenylpyridin-3-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((2-phenylpyridin-3-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-(methylsulfanyl)phenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-methoxyphenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-(dimethylamino)phenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-fluorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(pyridin-4-ylsulfanyl)ethyl)amino)benzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-(methylsulfonyl)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-(methylsulfonyl)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfonyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-(dimethylamino)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N,N-dimethyl-4-(phenylsulfonyl)butanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((3S,4R)-(phenylsulfanyl)pyrrolidin-4-yl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-4-ylsulfanyl)propyl)amino)benzenesulfonamide,

N-(4-(4-((3-(4-chlorophenyl)pyridin-4-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((3-(4-chlorophenyl)pyridin-4-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclopenten-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-bromo-1-cyclopenten-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((2-bromo-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-methoxyphenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-fluorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-N-(4-(4-((2-phenyl-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cycloocten-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((2-(4-(methylsulfanyl)phenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohepten-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohepten-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(morpholin-4-yl)ethoxy)piperidin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethylamino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(morpholin-4-yl)ethoxy)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethylamino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethylamino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidin-1-yl)benzoyl)-3-nitro-4-((1-((phenylsulfanyl)methyl)cyclopentyl)amino)benzene-sulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(dimethylamino)ethoxy)piperidin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(dimethylamino)ethoxy)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(dimethylamino)ethoxy)piperidin-1-yl)benzoyl)-3-nitro-4-((1-((phenylsulfanyl)methyl)cyclopentyl)amino)benzene-sulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(piperidin-1-yl)ethoxy)piperidin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(piperidin-1-yl)ethoxy)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-(2-(piperidin-1-yl)ethoxy)piperidin-1-yl)benzoyl)-3-nitro-4-((1-((phenylsulfanyl)methyl)cyclopentyl)amino)benzene-sulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1S)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-(2-(dimethylamino)ethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-(2-(dimethylamino)ethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-(2-(dimethylamino)ethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethylamino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-(2-(dimethylamino)ethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-(2-(morpholin-4-yl)ethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-(2-(morpholin-4-yl)ethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-N-(4-(4-((4′-(2-(morpholin-4-yl)ethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-(2-(morpholin-4-yl)ethoxy)(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxy-piperidin-1-yl)benzoyl)-4-(((1R)-3-(1H-imidazol-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-4-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)butyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide,

(4R)-4-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N,N-dimethyl-5-(phenylsulfanyl)pentanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-4-(dimethylamino)-1-((phenylsulfonyl)methyl)butyl)amino)-3-nitrobenzenesulfonamide,

2-(((3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butyl)(methyl)amino)-N,N-dimethylacetamide,

(3R)-N-(tert-butyl)-3-(4-(((4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butanamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N,N-diisopropyl-4-(phenylsulfanyl)butanamide,

(3R)-N-(tert-butyl)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N-methyl-4-(phenylsulfanyl)butanamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N-isopropyl-N-methyl-4-(phenylsulfanyl)butanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-3-oxo-1-((phenylsulfanyl)methyl)-3-(piperidin-1-yl)propyl)amino)benzenesulfonamide,

N-((5R)-5-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-6-(phenylsulfanyl)hexyl)-2-(dimethylamino)acetamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N,N-dimethyl-4-(phenylsulfanyl)butanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(1,1-dioxidothiomorpholin-4-yl)-3-oxo-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-4-(phenylsulfanyl)butanamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N-cyclopropyl-4-(phenylsulfanyl)butanamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N-cyclobutyl-4-(phenylsulfanyl)butanamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-3-oxo-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-3-oxo-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(azetidin-1-yl)-3-oxo-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N-(2-(morpholin-4-yl)ethyl)-4-(phenylsulfanyl)butanamide,

(3R)-3-(4-(((4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-nitroanilino)-N-methyl-4-(phenylsulfanyl)butanamide,

4-(((1R)-3-amino-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-cyano-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(tert-butylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(cyclopropylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(cyclobutylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(tert-butyl(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(piperidin-1-yl)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(4-hydroxypiperidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(4-acetylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(thiomorpholin-4-yl)propyl)aminoibenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2-(morpholin-4-yl)ethyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(piperazin-1-yl)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((3R)-3-hydroxypyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-((3R)-3-aminopyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(3-hydroxyazetidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(1,1-dioxidothiomorpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(1,3-benzodioxol-5-ylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

4-(((1R)-3-((1,3-benzodioxol-4-ylmethyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-2-ylmethyl)amino)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-((2-(pyridin-2-yl)ethyl)amino)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-((pyridin-4-ylmethyl)amino)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-ylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(methyl(pyridin-4-yl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(pyridin-3-ylamino)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2R,6S)-2,6-dimethylpiperidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-ylamino)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(4-(methoxyimino)piperidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitro-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(2H-tetrazol-5-yl)propyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(isopropylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

4-(((1R)-3-(bis(2-hydroxyethyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-4-(trifluoromethoxy)benzenesulfonamide;

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(isopropyl(methyl)amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(diethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-amino-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-2-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-fluorobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-2-(trifluoromethoxy)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-2,5-difluorobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-methylbenzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(diisopropylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-5-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cycloheken-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-5-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohepten-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitro-5-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-3-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-4-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3,5-difluorobenzenesulfonamide,

methyl5-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzoate,

5-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzoicacid,

5-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzoicacid,

5-(((4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzoicacid,

5-(((4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzamide,

5-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzamide,

methyl5-(((4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzoate,

methyl5-(((4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzoate,

methyl5-(((4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)amino)sulfonyl)-2-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-(trifluoromethyl)benzoate,

N-(4-(4-((2-(4-chlorophenyl)-1-cyclohexen-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1-((phenylsulfanyl)methyl)butyl)amino)-3-nitrobenzenesulfonamide,

tert-butyl3-((4-(4-((((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)piperazin-1-yl)carbonyl)phenylcarbamate,

N-(4-(4-(3-(dimethylamino)benzoyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-methyl-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-(((1S)-3-(dimethylamino)-1-methyl-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-(2-(1,3-dihydro-2H-isoindol-2-yl)benzyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-(2-(cyclohexylamino)benzyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(4-(4-(2-(isopropylamino)benzyl)piperazin-1-yl)benzoyl)-3-nitrobenzenesulfonamide,

N-(4-(4-(2-(benzylamino)benzyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3′-nitro-N-(4-(4-(2-(piperidin-1-yl)benzyl)piperazin-1-yl)benzoyl)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)piperazin-1-yl)benzoyl)-4-((cyclohexylmethyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((1,1′-biphenyl)-2-ylmethyl)-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1S)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-1-((phenylsulfanyl)methyl)-3-(pyrrolidin-1-yl)propyl)amino)-3-(trifluoromethyl)benzenesulfonamide,

N-(4-(4-((4-(4-chlorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4-(4-chlorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-2-fluoro-3-(trifluoromethyl)benzenesulfonamide,

N-(6-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)-1,2-benzisoxazol-3-yl)-3-nitro-4-((2-(phenylsulfanyl)ethylamino)benzenesulfonamide,

N-(6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-1,2-benzisoxazol-3-yl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(6-(4,4-dimethylpiperidin-1-yl)-1,2-benzisoxazol-3-yl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(6-(4,4-dimethylpiperidin-1-yl)-1,2-benzisoxazol-3-yl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(6-(4-(3,3-diphenylpropen-2-yl)piperazin-1-yl)-1,2-benzisoxazol-3-yl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(6-(4-(3,3-diphenylpropen-2-yl)piperazin-1-yl)-1,2-benzisoxazol-3-yl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-1,2-benzisoxazol-3-yl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-N-(6-(4,4-dimethylpiperidin-1-yl)-1,2-benzisoxazol-3-yl)-3-nitrobenzenesulfonamide,

N-(6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)-4-((1,1-dimethyl-2-(phenylsulfanyl)ethylamino)-3-nitrobenzenesulfonamide,

N-(6-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

N-(6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide,

N-(6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,and

N-(6-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,

or therapeutically acceptable salts, prodrugs or salts of prodrugsthereof.

Still another embodiment pertains to compositions for treating diseasesduring which are expressed one or more than one of antiapoptoticBcl-X_(L) protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-wprotein, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having formula (I).

Still another embodiment pertains to methods of treating disease in apatient during which is expressed one or more than one of antiapoptoticBcl-X_(L) protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-wprotein, said methods comprising administering to the patient atherapeutically effective amount of a compound having formula (I).

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having formula (I).

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound having formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which are expressed one or more than one of antiapoptoticBcl-X_(L) protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-wprotein, said compositions comprising an excipient and a therapeuticallyeffective amount ofN-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,or a therapeutically acceptable salt, prodrug or salt of a prodrugthereof.

Still another embodiment pertains to methods of treating disease in apatient during which is expressed one or more than one of antiapoptoticBcl-X_(L) protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-wprotein, said methods comprising administering to the patient atherapeutically effective amount ofN-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,or a therapeutically acceptable salt, prodrug or salt of a prodrugthereof.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount ofN-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethyl-amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,or a therapeutically acceptable salt, prodrug or salt of a prodrugthereof.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount ofN-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamide,or a therapeutically acceptable salt, prodrug or salt of a prodrugthereof.

Still another embodiment pertains to compositions for treating diseasesduring which are expressed one or more than one of antiapoptoticBcl-X_(L) protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-wprotein, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having formula (I) and atherapeutically effective amount of one additional therapeutic agent ormore than one additional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which is expressed one or more than one of antiapoptoticBcl-X_(L) protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-wprotein, said methods comprising administering to the patient atherapeutically effective amount of a compound having formula (I) and atherapeutically effective amount of one additional therapeutic agent ormore than one additional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow'cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having formula (I) and atherapeutically effective amount of one additional therapeutic agent ormore than one additional therapeutic agent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-tell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of the compound having formula (I) anda therapeutically effective amount of one additional therapeutic agentor more than one additional therapeutic agent.

Still another embodiment pertains to compositions for treating diseasesduring which are expressed one or more than one of antiapoptoticBcl-X_(L) protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-wprotein, said compositions comprising an excipient and a therapeuticallyeffective amount ofN-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,or a therapeutically acceptable salt, prodrug or salt of a prodrugthereof, and a therapeutically effective amount of one additionaltherapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which is expressed one or more than one of antiapoptoticBcl-X_(L) protein, antiapoptotic Bcl-2 protein or antiapoptotic Bcl-wprotein, said methods comprising administering to the patient atherapeutically effective amount ofN-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,or a therapeutically acceptable salt, prodrug or salt of a prodrugthereof, and a therapeutically effective amount of one additionaltherapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount ofN-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethyl-amino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,or a therapeutically acceptable salt, prodrug or salt of a prodrugthereof, and a therapeutically effective amount of one additionaltherapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount ofN-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,or a therapeutically acceptable salt, prodrug or salt of a prodrugthereof, and a therapeutically effective amount of one additionaltherapeutic agent or more than one additional therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letterswith numerical and/or alphabetical superscripts) and may be specificallyembodied.

It is meant to be understood that proper valences are maintained for allmoieties and combinations thereof, that monovalent moieties having morethan one atom are drawn from left to right and are attached throughtheir left ends, and that divalent moieties are also drawn from left toright.

It is also meant to be understood that a specific embodiment of avariable moiety herein may be the same or different as another specificembodiment having the same identifier.

The term “cyclic moiety,” as used herein, means arene, aryl,cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, heteroarene,heteroaryl, heterocycloalkane, heterocycloalkyl, heterocycloalkene,heterocycloalkenyl, spiroalkyl, spiroalkenyl, spiroheteroalkyl andspiroheteroalkenyl.

The term “arene,” as used herein, means benzene.

The term “aryl,” as used herein, means phenyl.

The term “cycloalkane,” as used herein, means C₃-cycloalkane,C₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane, C₇-cycloalkane,C₈-cycloalkane, C₉-cycloalkane, C₁₀-cycloalkane, C₁₁-cycloalkane,C₁₂-cycloalkane, C₁₃-cycloalkane and C₁₄-cycloalkane.

The term “cycloalkyl,” as used herein, means C₃-cycloalkyl,C₄-cycloalkyl, C₅-cycloalkyl C₆-cycloalkyl, C₇-cycloalkyl,C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl, C₁₁-cycloalkyl,C₁₂-cycloalkyl, C₁₃-cycloalkyl and C₁₄-cycloalkyl.

The term “cycloalkene,” as used herein, means C₄-cycloalkene,C₅-cycloalkene, C₆-cycloalkene, C₇-cycloalkene, C₈-cycloalkene,C₉-cycloalkene, C₁₀-cycloalkene, C₁₁-cycloalkene, C₁₂-cycloalkene,C₁₃-cycloalkene and C₁₄-cycloalkene.

The term “cycloalkenyl,” as used herein, means C₃-cycloalkenyl,C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl,C₈-cycloalkenyl, C₉-cycloalkenyl, C₁₀-cycloalkenyl, C₁₁-cycloalkenyl,C₁₂-cycloalkenyl, C₁₃-cycloalkenyl and C₁₄-cycloalkenyl.

The term “heteroarene,” as used herein, means furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine and 1,2,3-triazole.

The term “heteroaryl,” as used herein, means furanyl, imidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.

The term “heterocycloalkane,” as used herein, means cycloalkane havingone or two or three CH₂ moieties replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N and also means cycloalkane having one ortwo or three CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties replaced with N.

The term “heterocycloalkyl,” as used herein, means cycloalkyl having oneor two or three CH₂ moieties replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N and also means cycloalkyl having one ortwo or three CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties replaced with N.

The term “heterocycloalkene,” as used herein, means cycloalkene havingone or two or three CH₂ moieties replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N and also means cycloalkene having one ortwo or three CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties replaced with N.

The term “heterocycloalkenyl,” as used herein, means cycloalkenyl havingone or two or three CH₂ moieties replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N and also means cycloalkenyl having one ortwo or three CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties replaced with N.

The term “spiroalkyl,” as used herein, means C₂-spiroalkyl,C₃-spiroalkyl, C₄-spiroalkyl, C₅-spiroalkyl, C₆-spiroalkyl,C₇-spiroalkyl, C₈-spiroalkyl and C₉-spiroalkyl.

The term “spiroalkenyl,” as used herein, means C₂-spiroalkenyl,C₃-spiroalkenyl, C₄-spiroalkenyl, C₅-spiroalkenyl, C₆-spiroalkenyl,C₇-spiroalkenyl, C₈-spiroalkenyl and C₉-spiroalkenyl.

The term “spiroheteroalkyl,” as used herein, means spiroalkyl having oneor two CH₂ moieties replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH.

The term “spiroheteroalkenyl,” as used herein, means spiroalkenyl havingone or two CH₂ moieties replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N and also means spiroalkenyl having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties replacedwith N.

The term “alkenyl,” as used herein, means C₂-alkenyl, C₃-alkenyl,C₄-alkenyl, C₅-alkenyl and C₆-alkenyl.

The term “alkyl,” as used herein, means C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl and C₆-alkyl.

The term “alkynyl,” as used herein, means C₂-alkynyl, C₃-alkynyl,C₄-alkynyl, C₅-alkynyl and C₆-alkynyl.

The term “C₂-alkenyl,” as used herein, means ethenyl (vinyl).

The term “C₃-alkenyl,” as used herein, means 1-propen-1-yl,1-propen-2-yl (isopropenyl) and 1-propen-3-yl (allyl).

The term “C₄-alkenyl,” as used herein, means 1-buten-1-yl, 1-buten-2-yl,1,3-butadien-1-yl, 1,3-butadien-2-yl, 2-buten-1-yl, 3-buten-1-yl,3-buten-2-yl, 2-methyl-1-propen-1-yl and 2-methyl-2-propen-1-yl.

The term “C₅-alkenyl,” as used herein, means 2-methylene-3-buten-1-yl,2-methylenebut-1-yl, 2-methyl-1-buten-1-yl, 2-methyl-1,3-butadien-1-yl,2-methyl-2-buten-1-yl, 2-methyl-3-buten-1-yl, 2-methyl-3-buten-2-yl,3-methyl-1-buten-1-yl, 3-methyl-1-buten-2-yl,3-methyl-1,3-butadien-1-yl, 3-methyl-1,3-butadien-2-yl,3-methyl-2-buten-1-yl, 3-methyl-2-buten-2-yl, 3-methyl-3-buten-1-yl,3-methyl-3-buten-2-yl, 1-penten-1-yl, 1-penten-2-yl, 1-penten-3-yl,1,3-pentadien-1-yl, 1,3-penta-dien-2-yl, 1,3-pentadien-3-yl,1,4-pentadien-1-yl, 1,4-pentadien-2-yl, 1,4-pentadien-3-yl,2-penten-1-yl, 2-penten-2-yl, 2-penten-3-yl, 2,4-pentadien-1-yl,2,4-pentadien-2-yl, 3-penten-1-yl, 3-penten-2-yl, 4-penten-1-yl and4-penten-2-yl.

The term “C₆-alkenyl,” as used herein, means 2,2-dimethyl-3-buten-1-yl,2,3-dimethyl-1-buten-1-yl, 2,3-dimethyl-1,3-butadien-1-yl,2,3-dimethyl-2-buten-1-yl, 2,3-dimethyl-3-buten-1-yl,2,3-dimethyl-3-buten-2-yl, 3,3-dimethyl-1-buten-1-yl,3,3-dimethyl-1-buten-2-yl, 2-ethenyl-1,3-butadien-1-yl,2-ethenyl-2-buten-1-yl, 2-ethyl-1-buten-1-yl, 2-ethyl-1,3-butadien-1-yl,2-ethyl-2-buten-1-yl, 2-ethyl-3-buten-1-yl, 1-hexen-1-yl, 1-hexen-2-yl,1-hexen-3-yl, 1,3-hexadien-1-yl, 1,3-hexadien-2-yl, 1,3-hexadien-3-yl,1,3,5-hexatrien-1-yl, 1,3,5-hexatrien-2-yl, 1,3,5-hexatrien-3-yl,1,4-hexadien-1-yl, 1,4-hexadien-2-yl, 1,4-hexadien-3-yl,1,5-hexadien-1-yl, 1,5-hexadien-2-yl, 1,5-hexadien-3-yl, 2-hexen-1-yl,2-hexen-2-yl, 2-hexen-3-yl, 2,4-hexadien-1-yl, 2,4-hexadien2-yl,2,4-hexadien-3-yl, 2,5-hexadien-1-yl, 2,5-hexadien-2-yl,2,5-hexadien-3-yl, 3-hexen-1-yl, 3-hexen-2-yl, 3-hexen-3-yl,3,5-hexadien-1-yl, 3,5-hexadien-2-yl, 3,5-hexadien-3-yl, 4-hexen-1-yl,4-hexen-2-yl, 4-hexen-3-yl, 5-hexen-1-yl, 5-hexen-2-yl, 5-hexen-3-yl,2-methylene-3-methyl-3-buten-1-yl, 2-methylene-3-methylbut-1-yl,2-methylene-3-penten-1-yl, 2-methylene-4-penten-1-yl,2-methylenepent-1-yl, 2-methylenepent-3-yl, 3-methylene-1-penten-1-yl,3-methylene-1-penten-2-yl, 3-methylenepent-1-yl,3-methylene-1,4-pentadien-1-yl, 3-methylene-1,4-pentadien-2-yl,3-methylene-pent-2-yl, 2-methyl-1-penten-1-yl, 2-methyl-1-penten-3-yl,2-methyl-1,3-pentadien-1-yl, 2-methyl-1,3-pentadien-3-yl,2-methyl-1,4-pentadien-1-yl, 2-methyl-1,4-pentadien-3-yl,2-methyl-2-penten-1-yl, 2-methyl-2-penten-3-yl,2-methyl-2,4-pentadien-1-yl, 2-methyl-2,4-pentadien-3-yl,2-methyl-3-penten-.1-yl, 2-methyl-3-penten-2-yl, 2-methyl-3-penten-3-yl,2-methyl-4-penten-1-yl, 2-methyl-4-penten-2-yl, 2-methyl-4-penten-3-yl,3-methyl-1-penten-1-yl, 3-methyl-1-penten-2-yl,3-methyl-1,3-pentadien-1-yl, 3-methyl-1,3-pentadien-2-yl,3-methyl-1,4-pentadien-1-yl, 3-methyl-1,4-pentadien-2-yl,3-methyl-2-penten-1-yl, 3-methyl-2-penten-2-yl,3-methyl-2,4-pentadien-1-yl, 3-methyl-3-penten-1-yl,3-methyl-3-penten-2-yl, 3-methyl-4-penten-1-yl, 3-methyl-4-penten-2-yl,3-methyl-4-penten-3-yl, 4-methyl-1-penten-1-yl, 4-methyl-1-penten-2-yl,4-methyl-1-penten-3-yl, 4-methyl-1,3-pentadien-1-yl,4-methyl-1,3-pentadien-2-yl, 4-methyl-1,3-pentadien-3-yl,4-methyl-1,4-pentadien-1-yl, 4-methyl-1,4-pentadien-2-yl,4-methyl-1,4-pentadien-3-yl, 4-methylene-2-penten-3-yl,4-methyl-2-penten-1-yl, 4-methyl-2-penten-2-yl, 4-methyl-2-penten-3-yl,4-methyl-2,4-pentadien-1-yl, 4-methyl-2,4-pentadien-2-yl,4-methyl-3-penten-1-yl, 4-methyl-3-penten-2-yl, 4-methyl-3-penten-3-yl,4-methyl-4-penten-1-yl and 4-methyl-4-penten-2-yl.

The term “C₁-alkyl,” as used herein, means methyl. The term “C₂-alkyl,”as used herein, means ethyl. The term “C₃-alkyl,” as used herein, meansprop-1-yl and prop-2-yl (isopropyl).

The term “C₄-alkyl,” as used herein, means but-1-yl, but-2-yl,2-methylprop-1-yl and 2-methylprop-2-yl (tert-butyl).

The term “C₅-alkyl,” as used herein, means 2,2-dimethylprop-1-yl(neo-pentyl), 2-methylbut-1-yl, 2-methylbut-2-yl, 3-methylbut-1-yl,3-methylbut-2-yl, pent-1-yl, pent-2-yl and pent-3-yl.

The term “C₆-alkyl,” as used herein, means 2,2-dimethylbut-1-yl,2,3-dimethylbut-1-yl, 2,3-dimethylbut-2-yl, 3,3-dimethylbut-1-yl,3,3-dimethylbut-2-yl, 2-ethylbut-1-yl, hex-1-yl, hex-2-yl, hex-3-yl,2-methylpent-1-yl, 2-methylpent-2-yl, 2-methylpent-3-yl,3-methylpent-1-yl, 3-methylpent-2-yl, 3-methylpent-3-yl,4-methylpent-1-yl and 4-methylpent-2-yl.

The term “C₂-alkynyl,” as used herein, means ethynyl (acetylenyl).

The term “C₃-alkynyl,” as used herein, means 1-propyn-1-yl and2-propyn-1-yl (propargyl).

The term “C₄-alkynyl,” as used herein, means 1-butyn-1-yl,1,3-butadiyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl and 3-butyn-2-yl.

The term “C₅-alkynyl,” as used herein, means 2-methyl-3-butyn-1-yl,2-methyl-3-butyn-2-yl, 3-methyl-1-butyn-1-yl, 1,3-pentadiyn-1-yl,1,4-pentadiyn-1-yl, 1,4-pentadiyn-3-yl, 2,4-pentadiyn-1-yl,1-pentyn-1-yl, 1-pentyn-3-yl, 2-pentyn-1-yl, 3-pentyn-1-yl,3-pentyn-2-yl, 4-pentyn-1-yl and 4-pentyn-2-yl.

The term “C₆-alkynyl,” as used herein, means 2,2-dimethyl-3-butyn-1-yl,3,3-dimethyl-1-butyn-1-yl, 2-ethyl-3-butyn-1-yl, 2-ethynyl-3-butyn-1-yl,1-hexyn-1-yl, 1-hexyn-3-yl, 1,3-hexadiyn-1-yl, 1,3,5-hexatriyn-1-yl,1,4-hexadiyn-1-yl, 1,4-hexadiyn-3-yl, 1,5-hexadiyn-1-yl,1,5-hexadiyn-3-yl, 2-hexyn-1-yl, 2,5-hexadiyn-1-yl, 3-hexyn-1-yl,3-hexyn-2-yl, 3,5-hexadiyn-2-yl, 4-hexyn-1-yl, 4-hexyn-2-yl,4-hexyn-3-yl, 5-hexyn-1-yl, 5-hexyn-2-yl, 5-hexyn-3-yl,2-methyl-3-pentyn-1-yl, 2-methyl-3-pentyn-2-yl, 2-methyl-4-pentyn-1-yl,2-methyl-4-pentyn-2-yl, 2-methyl-4-pentyn-3-yl, 3-methyl-1-pentyn-1-yl,3-methyl-4-pentyn-1-yl, 3-methyl-4-pentyn-2-yl,3-methyl-1,4-pentadiyn-1-yl, 3-methyl-1,4-pentadiyn-3-yl,3-methyl-4-pentyn-1-yl, 3-methyl-4-pentyn-3-yl, 4-methyl-1-pentyn-1-yland 4-methyl-2-pentyn-1-yl.

The term “C₄-cycloalkane,” as used herein, means cyclobutane.

The term “C₅-cycloalkane,” as used herein, means cyclopentane.

The term “C₆-cycloalkane,” as used herein, means cyclohexane.

The term “C₇-cycloalkane,” as used herein, means cycloheptane.

The term “C₈-cycloalkane,” as used herein, means cyclooctane.

The term “C₉-cycloalkane,” as used herein, means cyclononane.

The term “C₁₀-cycloalkane,” as used herein, means cyclodecane.

The term “C₁₁-cycloalkane,” as used herein, means cycloundecane.

The term “C₁₂-cycloalkane,” as used herein, means cyclododecane.

The term “C₁₃-cycloalkane,” as used herein, means cyclotridecane.

The term “C₁₄-cycloalkane,” as used herein, means cyclotetradecane.

The term “C₄-cycloalkene,” as used herein, means cyclobutene and1,3-cyclobutadiene.

The term “C₅-cycloalkene,” as used herein, means cyclopentene and1,3-cyclopentadiene.

The term “C₆-cycloalkene,” as used herein, means cyclohexene,1,3-cyclohexadiene and 1,4-cyclohexadiene.

The term “C₇-cycloalkene,” as used herein, means cycloheptene and1,3-cycloheptadiene.

The term “C₈-cycloalkene,” as used herein, means cyclooctene,1,3-cyclooctadiene, 1,4-cyclooctadiene, 1,5-cyclooctadiene,1,3,5-cyclooctatriene and 1,3,6-cyclooctatriene.

The term “C₉-cycloalkene,” as used herein, means cyclononene,1,3-cyclononadiene, 1,4-cyclononadiene, 1,5-cyclononadiene,1,3,5-cyclononatriene, 1,3,6-cyclononatriene, 1,3,7-cyclononatriene and1,3,5,7-cyclononatetraene.

The term “C₁₀-cycloalkene,” as used herein, means cyclodecene,1,3-cyclodecadiene, 1,4-cyclodecadiene, 1,5-cyclodecadiene,1,6-cyclodecadiene, 1,3,5-cyclodecatriene, 1,3,6-cyclodecatriene,1,3,5,7-cyclodecatetraene, 1,3,5,8-cyclodecatetraene and1,3,6,8-cyclodecatetraene.

The term “C₁₁-cycloalkene,” as used herein, means cycloundecene,1,3-cycloundecadiene, 1,4-cycloundecadiene, 1,5-cycloundecadiene,1,6-cycloundecadiene, 1,3,5-cycloundecatriene, 1,3,6-cycioundecatriene,1,3,7-cycloundecatriene, 1,4,7-cycloundecatriene,1,4,8-cycloundecatriene, 1,3,5,7-cycloundecatetraene,1,3,5,8-cycloundecatetraene, 1,3,6,8-cycloundecatetraene and1,3,5,7,9-cycloundecapentaene.

The term “C₁₂-cycloalkene,” as used herein, means cyclododecene,1,3-cyclododecadiene, 1,4-cyclododecadiene, 1,5-cyclododecadiene,1,6-cyclododecadiene, 1,7-cyclododecadiene, 1,3,5-cyclododecatriene,1,3,6-cyclododecatriene, 1,3,7-cyclododecatriene,1,3,8-cyclododecatriene, 1,4,7-cyclododecatriene,1,4,8-cyclododecatriene, 1,5,9-cyclododecatriene,1,3,5,7-cyclododecatetraene, 1,3,5,8-cyclododecatetraene,1,3,5,9-cyclododecatetraene, 1,3,6,8-cyclododecatetraene,1,3,6,9-cyclododecatetraene, 1,3,6,10-cyclododecatetraene,1,3,7,9-cyclododecatetraene, 1,4,7,10-cyclododecatetraene,1,3,5,7,9-cyclododecapentaene, 1,3,5,7,10-cyclododecapentaene and1,3,5,8,10-cyclododecapentaene.

The term “C₁₃-cycloalkene,” as used herein, means 1,3-cyclotridecadiene,1,4-cyclotridecadiene, 1,5-cyclotridecadiene, 1,6-cyclotridecadiene,1,7-cyclotridecadiene, 1,3,5-cyclotridecatriene,1,3,6-cyclotridecatriene, 1,3,7-cyclotridecatriene,1,3,8-cyclotridecatriene, 1,4,7-cyclotridecatriene,1,4,8-cyclotridecatriene, 1,4,9-cyclotridecatriene,1,5,9-cyclotridecatriene, 1,3,5,7-cyclotridecatetraene,1,3,5,8-cyclotridecatetraene, 1,3,5,9-cyclotridecatetraene,1,3,6,8-cyclotridecatetraene, 1,3,6,9-cyclotridecatetraene,1,3,6,10-cyclotridecatetraene, 1,3,6,11-cyclotridecatetraene,1,3,7,9-cyclotridecatetraene, 1,3,7,10-cyclotridecatetraene,1,4,7,10-cyclotridecatetraene, 1,3,6,11-cyclotridecatetraene,1,3,5,7,9-cyclotridecapentaene, 1,3,5,7,10-cyclotridecapentaene,1,3,5,8,10-cyclotridecapentaene, 1,3,5,8,11-cyclotridecapentaene,1,3,6,8,11-cyclotridecapentaene and 1,3,5,7,9,11-cyclotridecahexaene.

The term “C₁₄-cycloalkene,” as used herein, means cyclotetradecene,1,3-cyclotetradecadiene, 1,4-cyclotetradecadiene,1,5-cyclotetradecadiene, 1,6-cyclotetradecadiene,1,7-cyclotetradecadiene, 1,8-cyclotetradecadiene,1,3,5-cyclotetradecatriene, 1,3,6-cyclotetradecatriene,1,3,7-cyclotetradecatriene, 1,3,8-cyclotetradecatriene,1,3,9-cyclotetradecatriene, 1,4,7-cyclotetradecatriene,1,4,8-cyclotetradecatriene, 1,4,9-cyclotetradecatriene,1,5,9-cyclotetradecatriene, 1,5,10-cyclotetradecatriene,1,3,5,7-cyclotetradecatetraene, 1,3,5,8-cyclotetradecatetraene,1,3,5,9-cyclotetradecatetraene, 1,3,5,10-cyclotetradecatetraene,1,3,6,8-cyclotetradecatetraene, 1,3,6,9-cyclotetradecatetraene,1,3,6,10-cyclotetradecatetraene, 1,3,6,11-cyclotetradecatetraene,1,3,6,12-cyclotetradecatetraene, 1,3,7,9-cyclotetradecatetraene,1,3,7,10-cyclotetradecatetraene, 1,3,7,11-cyclotetradecatetraene,1,3,8,10-cyclotetradecatetraene, 1,4,7,10cyclotetradecatetraene,1,4,7,11-cyclotetradecatetraene, 1,4,8,11-cyclotetradecatetraene,1,3,5,7,9-cyclotetradecapentaene, 1,3,5,7,10-cyclotetradecapentaene,1,3,5,7,11-cyclotetradecapentaene, 1,3,5,8,10-cyclotetradecapentaene,1,3,5,8,11-cyclotetradecapentaene, 1,3,5,8,12-cyclotetradecapentaene,1,3,5,9,11-cyclotetradecapentaene, 1,3,5,8,11-cyclotetradecapentaene,1,3,6,8,11-cyclotetradecapentaene, 1,3,6,9,11-cyclotetradecapentaene,1,3,6,9,12-cyclotetradecapentaene, 1,3,5,8,11-cyclotetradecapentaene,1,3,5,8,12-cyclotetradecapentaene, 1,3,5,7,9,11-cyclotetradecahexaene,1,3,5,7,9,12-cyclotetradecahexaene, 1,3,5,7,10,12-cyclotetradecahexaene,1,3,5,8,10,12-cyclotetradecahexaene and1,3,5,7,9,11,13-cyclotetradecaheptaene.

The term “C₃-cycloalkenyl,” as used herein, means cycloprop-1-en-1-yland cycloprop-2-en-1-yl.

The term “C₄-cycloalkenyl,” as used herein, means cyclobut-1-en-1-yl andcyclobut-2-en-1-yl.

The term “C₅-cycloalkenyl,” as used herein, means cyclopent-1-en-1-yl,cyclopent-2-en-1-yl, cyclopent-3-en-1-yl and cyclopenta-1,3-dien-1-yl.

The term “C₆-cycloalkenyl,” as used herein, means cyclohex-1-en-1-yl,cyclohex-2-en-1-yl, cyclohex-3-en-1-yl, cyclohexa-1,3-dien-1-yl,cyclohexa-1,4-dien-1-yl, cyclohexa-1,5-dien-1-yl,cyclohexa-2,4-dien-1-yl and cyclohexa-2,5-dien-1-yl.

The term “C₇-cycloalkenyl,” as used herein, meansbicyclo[2.2.1]hept-2-en-1-yl, bicyclo[2.2.1]hept-2-en-2-yl,bicyclo[2.2.1]hept-2-en-5-yl, bicyclo[2.2.1]hept-2-en-7-yl,bicyclo[2.2.1]hepta-2,5-dien-1-yl, bicyclo[2.2.1]hepta-2,5-dien-2-yl,bicyclo[2.2.1]hepta-2,5-dien-7-yl, cyclohept-1-en-1-yl,cyclohept-2-en-1-yl, cyclohept-3-en-1-yl, cyclohept-4-en-1-yl,cyclohepta-1,3-dien-1-yl, cyclohepta-1,4-dien-1-yl,cyclohepta-1,5-dien-1-yl, cyclohepta-1,6-dien-1-yl,cyclohepta-2,4-dien-1-yl, cyclohepta-2,5-dien-1-yl,cyclohepta-2,6-dien-1-yl, cyclohepta-3,5-dien-1-yl,cyclohepta-1,3,5-trien-1-yl, cyclohepta-1,3,6-trien-1-yl,cyclohepta-1,4,6-trien-1-yl and cyclohepta-2,4,6-trien-1-yl.

The term “C₈-cycloalkenyl,” as used herein, meansbicyclo[2.2.2]oct-2-en-1-yl,bicyclo[2.2.2]oct-2-en-2-yl,bicyclo[2.2.2]oct-2-en-5-yl,bicyclo[2.2.2]oct-2-en-7-yl, bicyclo[2.2.2]octa-2,5-dien-1-yl,bicyclo[2.2.2]octa-2,5-dien-2-yl, bicyclo[2.2.2]octa-2,5-dien-7-yl,bicyclo[2.2.2]octa-2,5,7-trien-1-yl, bicyclo[2.2.2]octa-2,5,7-trien-2-ylcyclooct-1-en-1-yl, cyclooct-2-en-1-yl, cyclooct-3-en-1-yl,cyclooct-4-en-1-yl, cycloocta-1,3-dien-1-yl, cycloocta-1,4-dien-1-yl,cycloocta-1,5-dien-1-yl, cycloocta-1,6-dien-1-yl,cycloocta1,7-dien-1-yl, cycloocta-2,4-dien-1-yl,cycloocta-2,5-dien-1-yl, cycloocta-2,6-dien-1-yl,cycloocta-2,7-dien-1-yl, cycloocta-3,5-dien-1-yl,cycloocta-3,6-dien-1-yl, cycloocta-1,3,5-trien-1-yl,cycloocta-1,3,6-trien-1-yl, cycloocta-1,3,7-trien-1-yl,cycloocta-1,4,6-trien-1-yl, cycloocta-1,4,7-trien-1-yl,cycloocta-1,5,7-trien-1-yl, cycloocta-2,4,6-trien-1-yl,cycloocta-2,4,7-trien-1-yl, cycloocta-2,5,7-trien-1-yl andcycloocta-1,3,5,7-tetraen-1-yl.

The term “C₉-cycloalkenyl,” as used herein, means cyclonon-1-en-1-yl,cyclonon-2-en-1-yl, cyclonon-3-en-1-yl, cyclonon-4-en-1-yl,cyclonon-5-en-1-yl, cyclonona-1,3-dien-1-yl, cyclonona-1,4-dien-1-yl,cyclonona-1,5-dien-1-yl, cyclonona-1,6-dien-1-yl,cyclonona-1,7-dien-1-yl, cyclonona-1,8-dien-1-yl,cyclonona-2,4-dien-1-yl, cyclonona-2,5-dien-1-yl,cyclonona-2,6-dien-1-yl, cyclonona-2,7-dien-1-yl,cyclonona-2,8-dien-1-yl, cyclonona-3,5-dien-1-yl,cyclonona-3,6-dien-1-yl, cyclonona-3,7-dien-1-yl,cyclonona-4,6-dien-1-yl, cyclonona-1,3,5-trien-1-yl,cyclonona-1,3,6-trien-1-yl, cyclonona-1,3,7-trien-1-yl,cyclonona-1,3,8-trien-1-yl, cyclonona-1,4,6-trien-1-yl,cyclonona-1,4,7-trien-1-yl, cyclonona-1,4,8-trien-1-yl,cyclonona-1,5,7-trien-1-yl, cyclonona-1,5,8-trien-1-yl,cyclonona-1,6,8-trien-1-yl, cyclonona-2,4,8-trien-1-yl,cyclonona-2,4,6-trien-1-yl, cyclonona-2,4,7-trien-1-yl,cyclonona-2,4,8-trien-1-yl, cyclonona-2,5,7-trien-1-yl,cyclonona-2,5,8-trien-1-yl, cyclonona-1,3,5,7-tetraen-1-yl,cyclonona-1,3,5,8-tetraen-1-yl, cyclonona-1,3,6,8-tetraen-1-yl,cyclonona-1,4,6,8-tetraen-1-yl and cyclonona-2,4,6,8-tetraen-1-yl.

The term “C₁₀-cycloalkenyl,” as used herein, means cyclodec-1-en-1-yl,cyclodec-2-en-1-yl, cyclodec-3-en-1-yl, cyclodec-4-en-1-yl,cyclodec-5-en-1-yl, cyclodeca-1,3-dien-1-yl, cyclodeca-1,4-dien-1-yl,cyclodeca-1,5-dien-1-yl, cyclodeca-1,6-dien-1-yl,cyclodeca-1,7-dien-1-yl, cyclodeca-1,8-dien-1-yl,cyclodeca-1,9-dien-1-yl, cyclodeca-2,4-dien-1-yl,cyclodeca-2,5-dien-1-yl, cyclodeca-2,6-dien-1-yl,cyclodeca-2,7-dien-1-yl, cyclodeca-2,8-dien-1-yl,cyclodeca-2,9-dien-1-yl, cyclodeca-3,5-dien-1-yl,cyclodeca-3,6-dien-1-yl, cyclodeca-3,7-dien-1-yl,cyclodeca-3,8-dien-1-yl, cyclodeca-4,6-dien-1-yl,cyclodeca-4,7-dien-1-yl, cyclodeca-1,3,5-trien-1-yl,cyclodeca-1,3,6-trien-1-yl, cyclodeca-1,3,7-trien-1-yl,cyclodeca-1,3,8-trien-1-yl, cyclodeca-1,3,9-trien-1-yl,cyclodeca-1,4,6-trien-1-yl, cyclodeca-1,4,7-trien-1-yl,cyclodeca-1,4,8-trien-1-yl, cyclodeca-1,4,9-trien-1-yl,cyclodeca-1,5,7-trien-1-yl, cyclodeca-1,5,8-trien-1-yl,cyclodeca-1,5,9-trien-1-yl, cyclodeca-1,6,8-trien-1-yl,cyclodeca-1,6,9-trien-1-yl, cyclodeca-1,7,9-trien-1-yl,cyclodeca-2,4,6-trien-1-yl, cyclodeca-2,4,7-trien-1-yl,cyclodeca-2,4,8-trien-1-yl, cyclodeca-2,4,9-trien-1-yl,cyclodeca-2,5,7-trien-1-yl, cyclodeca-2,5,8-trien-1-yl,cyclodeca-2,5,9-trien-1-yl, cyclodeca-2,6,8-trien-1-yl,cyclodeca-3,5,7-trien-1-yl, cyclodeca-3,5,8-trien-1-yl,cyclodeca-1,3,5,7-tetraen-1-yl, cyclodeca-1,3,5,8-tetraen-1-yl,cyclodeca-1,3,5,9-tetraen-1-yl, cyclodeca-1,3,6,8-tetraen-1-yl,cyclodeca-1,3,6,9-tetraen-1-yl, cyclodeca-1,3,7,9-tetraen-1-yl,cyclodeca-1,4,6,8-tetraen-1-yl, cyclodeca-1,4,6,9-tetraen-1-yl,cyclodeca-1,4,7,9-tetraen-1-yl, cyclodeca-1,5,7,9-tetraen-1-yl,cyclodeca-2,4,6,8-tetraen-1-yl, cyclodeca-2,4,6,9-tetraen-1-yl,cyclodeca-2,4,7,9-tetraen-1-yl and cyclodeca-1,3,5,7,9-pentaen-1-yl.

The term “C₁₁-cycloalkenyl,” as used herein, means cycloundec-1-en-1-yl,cycloundec-2-en-1-yl, cycloundec-3-en-1-yl, cycloundec-4-en-1-yl,cycloundec-5-en-1-yl, cycloundec-6-en-1-yl, cycloundeca-1,3-dien-1-yl,cycloundeca-1,4-dien-1-yl, cycloundeca-1,5-dien-1-yl,cycloundeca-1,6-dien-1-yl, cycloundeca-1,7-dien-1-yl,cycloundoca-1,8-dien-1-yl, cycloundeca-1,9-dien-1-yl,cycloundeca-1,10-dien-1-yl, cycloundeca-2,4-dien-1-yl,cycloundeca-2,5-dien-1-yl, cycloundeca-2,6-dien-1-yl,cycloundeca-2,7-dien-1-yl, cycloundeca-2,8-dien-1-yl,cycloundeca-2,9-dien-1-yl, cycloundeca-2,10-dien-1-yl,cycloundeca-3,5-dien-1-yl, cycloundeca-3,6-dien-1-yl,cycloundeca-3,7-dien-1-yl, cycloundeca-3,8-dien-1-yl,cycloundeca-3,9-dien-1-yl, cycloundeca-4,6-dien-1-yl,cycloundeca-4,7-dien-1-yl, cycloundeca-4,8-dien-1-yl,cycloundeca-5,7-dien-1-yl, cycloundeca-1,3,5-trien-1-yl,cycloundeca-1,3,6-trien-1-yl, cycloundeca-1,3,7-trien-1-yl,cycloundeca-1,3,8-trien-1-yl, cycloundeca-1,3,9-trien-1-yl,cycloundeca-1,3,10-trien-1-yl, cycloundeca-1,4,6-trien-1-yl,cycloundeca-1,4,7-tri-en-1-yl, cycloundeca-1,4,8-trien-1-yl,cycloundeca-1,4,9-trien-1-yl, cycloundeca-1,4,10-triers-1-yl,cycloundeca-1,5,7-trien-1-yl, cycloundeca-1,5,8-trien-1-yl,cycloundeca-1,5,9-trien-1-yl, cycloundeca-1,5,10-trien-1-yl,cycloundeca-1,6,8-trien-1-yl, cycloundeca-1,6,9-trien-1-yl,cycloundeca-1,6,10-trien-1-yl, cycloundeca-1,7,9-trien-1-yl,cycloundeca-1,7,10-trien-1-yl, cycloundeca-1,8,10-trien-1-yl,cycloundeca-2,4,6-trien-1-yl, cycloundeca-2,4,7-trien-1-yl,cycloundeca-2,4,8-trien-1-yl, cycloundeca-2,4,9-trien-1-yl,cycloundeca-2,4,10-trien-1-yl, cycloundeca-2,5,7-trien-1-yl,cycloundeca-2,5,8-trien-1-yl, cycloundeca-2,5,9-trien-1-yl,cycloundeca-2,5,10-tri-en-1-yl, cycloundeca-2,6,8-trien-1-yl,cycloundeca-2,6,9-trien-1-yl, cycloundeca-2,6,10-trien-1-yl,cycloundeca-2,7,9-trien-1-yl, cycloundeca-3,5,7-trien-1-yl,cycloundeca-3,5,8-trien-1-yl, cycloundeca-3,5,9-trien-1-yl,cycloundeca-3,6,8-trien-1-yl, cycloundeca-3,6,9-trien-1-yl,cycloundeca-4,6,8-trien-1-yl, cycloundeca-1,3,5,7-tetraen-1-yl,cycloundeca-1,3,5,8-tetraen-1-yl, cycloundeca-1,3,5,9-tetraen-1-yl,cycloundeca-1,3,5,10-tetraen-1-yl, cycloundeca-1,3,6,8-tetraen-1-yl,cycloundeca-1,3,6,9-tetraen-1-yl, cycloundeca-1,3,6,10-tetraen-1-yl,cycloundeca-1,3,7,9-tetraen-1-yl, cycloundeca-1,3,7,10-tetraen-1-yl,cycloundeca-1,3,8,10-tetraen-1-yl, cycloundeca-1,4,6,8-tetraen-1-yl,cycloundeca-1,4,6,9-tetraen-1-yl, cycloundeca-1,4,6,10-tetraen-1-yl,cycloundeca-1,4,8,10-tetraen-1-yl, cycloundeca-1,5,7,9-tetraen-1-yl,cycloundeca-1,5,7,10-tetraen-1-yl, cycloundeca-1,5,8,10-tetraen-1-yl,cycloundeca-1,6,8,10-tetraen-1-yl, cycloundeca-2,4,6,8-tetraen-1-yl,cycloundeca-2,4,6,9-tetraen-1-yl, cycloundeca-2,4,6,10-tetraen-1-yl,cycloundeca-2,4,7,9-tetraen-1-yl, cycloundeca-2,5,7,9-tetraen-1-yl,cycloundeca-3,5,7,9-tetraen-1-yl, cycloundeca-1,3,5,7,9-pentaenyl,cycloundeca-1,3,5,7,10-pentaenyl, cycloundeca-1,3,5,8,10-pentaenyl,cycloundeca-1,3,6,8,10-pentaenyl, cycloundeca-1,4,6,8,10-pentaenyl andcycloundeca-2,4,6,8,10-pentaenyl.

The term “C₁₂-cycloalkenyl,” as used herein, means cyclododec-1-en-1-yl,cyclododec-2-en-1-yl, cyclododec-3-en-1-yl, cyclododec-4-en-1-yl,cyclododec-5-en-1-yl, cyclododec-6-en-1-yl, cyclododeca-1,3-dien-1-yl,cyclododeca-1,4-dien-1-yl, cyclododeca-1,5-dien-1-yl,cyclododeca-1,6-dien-1-yl, cyclododeca-1,7-dien-1-yl,cyclododeca-1,8-dien-1-yl, cyclododeca-1,9-dien-1-yl,cyclododeca-1,10-dien-1-yl, cyclododeca-1,11-dien-1-yl,cyclododeca-2,4-dien-1-yl, cyclododeca-2,5-dien-1-yl,cyclododeca-2,6-dien-1-yl, cyclododeca-2,7-dien-1-yl,cyclododeca-2,8-dien-1-yl, cyclododeca-2,9dien-1-y1,cyclododeca-2,10-dien-1-yl, cyclododeca-2,11-dien-1-yl,cyclododeca-3,5-dien-1-yl, cyclododeca-3,6-dien-1-yl,cyclododeca-3,7-dien-1-yl, cyclododeca-3,8-dien-1-yl,cyclododeca-3,9-dien-1-yl, cyclododeca-3,10-dien-1-yl,cyclododeca-3,11-dien-1-yl, cyclododeca-4,6-dien-1-yl,cyclododeca-4,7-dien-1-yl, cyclododeca-4,8-dien-1-yl,cyclododeca-4,9-dien-1-yl, cyclododeca-5,7-dien-1-yl,cyclododeca-5,8-dien-1-yl, cyclododeca-1,3,5-trien-1-yl,cyclododeca-1,3,6-trien-1-yl, cyclododeca-1,3,7-trien-1-yl,cyclododeca-1,3,8-trien-1-yl, cyclododeca-1,3,9-trien-1-yl,cyclododeca-1,3,10-trien-1-yl, cyclododeca-1,3,11-trien-1-yl,cyclododeca-1,4,6-trien-1-yl, cyclododeca-1,4,7-trien-1-yl,cyclododeca-1,4,8-trien-1-yl, cyclododeca-1,4,9-trien-1-yl,cyclododeca-1,4,10-trien-1-yl, cyclododeca-1,4,11-trien-1-yl,cyclododeca-1,5,7-trien-1-yl, cyclododeca-1,5,8-trien-1-yl,cyclododeca-1,5,9-trien-1-yl, cyclododeca-1,5,10-trien-1-yl,cyclododeca-1,5,11-trien-1-yl, cyclododeca-1,6,8-trien-1-yl,cyclododeca-1,6,9-trien-1-yl, cyclododeca-1,6,10-trien-1-yl,cyclododeca-1,6,11-trien-1-yl, cyclododeca-1,7,9-trien-1-yl,cyclododeca-1,7,10-trien-1-yl, cyclododeca-1,7,11-trien-1-yl,cyclododeca-1,8,10-trien-1-yl, cyclododeca-1,8,11-trien-1-yl,cyclododeca-1,9,11-trien-1-yl, cyclododeca-2,4,6-trien-1-yl,cyclododeca-2,4,7-trien-1-yl, cyclododeca-2,4,8-trien-1-yl,cyclododeca-2,4,9-trien-1-yl, cyclododeca-2,4,10-trien-1-yl,cyclododeca-2,4,11-trien-1-yl, cyclododeca-2,5,7-trien-1-yl,cyclododeca-2,5,8-trien-1-yl, cyclododeca-2,5,9-trien-1-yl,cyclododeca-2,5,10-trien-1-yl, cyclododeca-2,5,11-trien-1-yl,cyclododeca-2,6,8-trien-1-yl, cyclododeca-2,6,9-trien-1-yl,cyclododeca-2,6,10-trien-1-yl, cyclododeca-2,6,11-trien-1-yl,cyclododeca-2,7,9-trien-1-yl, cyclododeca-2,7,10-trien-1-yl,cyclododeca-2,8,10-trien-1-yl, cyclododeca-3,5,7-trien-1-yl,cyclododeca-3,5,8-trien-1-yl, cyclododeca-3,5,9-trien-1-yl,cyclododeca-3,5,10-trien-1-yl, cyclododeca-3,6,8-trien-1-yl,cyclododeca-3,6,9-trien-1-yl, cyclododeca-3,6,10-trien-1-yl,cyclododeca-3,7,9-trien-1-yl, cyclododeca-4,6,8-trien-1-yl,cyclododeca-4,6,9-trien-1-yl, cyclododeca-1,3,5,7-tetraen-1-yl,cyclododeca-1,3,5,8-tetraen-1-yl, cyclododeca-1,3,5,9-tetraen-1-yl,cyclododeca-1,3,5,10-tetraen-1-yl, cyclododeca-1,3,5,11-tetraen-1-yl,cyclododeca-1,3,6,8-tetraen-1-yl, cyclododeca-1,3,6,9-tetraen-1-yl,cyclododeca-1,3,6,10-tetraen-1-yl, cyclododeca-1,3,6,11-tetraen-1-yl,cyclododeca-1,3,7,9-tetraen-1-yl, cyclododeca-1,3,7,10-tetraen-1-yl,cyclododeca-1,3,7,11-tetraen-1-yl, cyclododeca-1,3,8,10-tetraen-1-yl,cyclododeca-1,3,8,11-tetraen-1-yl, cyclododeca-1,3,9,11-tetraen-1-yl,cyclododeca-1,4,6,8-tetraen-1-yl, cyclododeca-1,4,6,9-tetraen-1-yl,cyclododeca-1,4,6,10-tetraen-1-yl, cyclododeca-1,4,6,11-tetraen-1-yl,cyclododeca-1,4,7,9-tetraen-1-yl, cyclododeca-1,4,7,10-tetraen-1-yl,cyclododeca-1,4,7,11-tetraen-1-yl, cyclododeca-1,4,8,10-tetraen-1-yl,cyclododeca-1,4,8,11-tetraen-1-yl, cyclododeca-1,4,9,11-tetraen-1-yl,cyclododeca-1,5,7,9-tetraen-1-yl, cyclododeca-1,5,7,10-tetraen-1-yl,cyclododeca-1,5,7,11-tetraen-1-yl, cyclododeca-1,5,8,10-tetraen-1-yl,cyclododeca-1,5,8,11-tetraen-1-yl, cyclododeca-1,5,9,11-tetraen-1-yl,cyclododeca-1,6,8,10-tetraen-1-yl, cyclododeca-1,6,8,11-tetraen-1-yl,cyclododeca-1,6,9,11-tetraen-1-yl, cyclododeca-1,7,9,11-tetraen-1-yl,cyclododeca-2,4,6,8-tetraen-1-yl, cyclododeca-2,4,6,9-tetraen-1-yl,cyclododeca-2,4,6,10-tetraen-1-yl, cyclododeca-2,4,6,11-tetraen-1-yl,cyclododeca-2,4,7,9-tetraen-1-yl, cyclododeca-2,4,7,10-tetraen-1-yl,cyclododeca-2,4,7,11-tetraen-1-yl, cyclododeca-2,4,8,10-tetraen-1-yl,cyclododeca-2,4,8,11-tetraen-1-yl, cyclododeca-2,4,9,11-tetraen-1-yl,cyclododeca-2,5,7,9-tetraen-1-yl, cyclododeca-2,5,7,10-tetraen-1-yl,cyclododeca-2,5,7,11-tetraen-1-yl, cyclododeca-2,5,8,10-tetraen-1-yl,cyclododeca-2,5,3,11-tetraen-1-yl, cyclododeca-2,6,8,10-tetraen-1-yl,cyclododeca-3,5,7,9-tetraen-1-yl, cyclododeca-3,5,7,10-tetraen-1-yl,cyclododeca-3,5,8,10-tetraen-1-yl, cyclododeca-1,3,5,7,9-pentaen-1-yl,cyclododeca-1,3,5,7,10-pentaen-1-yl,cyclododeca-1,3,5,7,11-pentaen-1-yl,cyclododeca-1,3,5,8,10-pentaen-1-yl,cyclododeca-1,3,5,8,11-pentaen-1-yl,cyclododeca-1,3,5,9,11-pentaen-1-yl,cyclododeca-1,3,6,8,10-pentaen-1-yl,cyclododeca-1,3,6,8,11-pentaen-1-yl,cyclododeca-1,3,6,9,11-pentaen-1-yl,cyclododeca-1,3,7,9,11-pentaen-1-yl,cyolododeca-1,4,6,8,10-pentaen-1-yl,cyclododeca-1,4,6,8,11-pentaen-1-yl,cyclododeca-1,4,6,9,11-pentaen-1-yl,cyclododeca-1,4,7,9,11-pentaen-1-yl,cyclododeca-1,5,7,9,11-pentaen-1-yl,cyclododeca-2,4,6,8,10-pentaen-1-yl,cyclododeca-2,4,6,8,11-pentaen-1-yl, cyclododeca-2,4,6,9,11-pentaen-1-yland cyclododeca-1,3,5,7,9,11-hexaen-1-yl.

The term “C₁₃-cycloalkenyl,” as used herein, meanscyclotridec-1-en-1-yl, cyclotridec-2-en-1-yl, cyclotridec-3-en-1-yl,cyclotridec-4-en-1-yl, cyclotridec-5-en-1-yl, cyclotridec-6-en-1-yl,cyclotridec-7-en-1-yl, cyclotrideca-1,3-dien-1-yl,cyclotrideca-1,4-dien-1-yl, cyclotrideca-1,5-dien-1-yl,cyclotrideca-1,6-dien-1-yl, cyclotrideca-1,7-dien-1-yl,cyclotrideca-1,8-dien-1-yl, cyclotrideca-1,9-dien-1-yl,cyclotrideca-1,10-dien-1-yl, cyclotrideca-1,11-dien-1-yl,cyclotrideca-1,12-dien-1-yl, cyclotrideca-2,4-dien-1-yl,cyclotrideca-2,5-dien-1-yl, cyclotrideca-2,6-dien-1-yl,cyclotrideca-2,7-dien-1-yl, cyclotrideca-2,8-dien-1-yl,cyclotrideca-2,9-dien-1-yl, cyclotrideca-2,10-dien-1-yl,cyclotrideca-2,11-dien-1-yl, cyclotrideca-2,12-dien-1-yl,cyclotrideca-3,5-dien-1-yl, cyclotrideca-3,6-dien-1-yl,cyclotrideca-3,7-dien-1-yl, cyclotrideca-3,8-dien-1-yl,cyclotrideca-3,9-dien-1-yl, cyclotrideca-3,10-dien-1-yl,cyclotrideca-3,11-dien-1-yl, cyclotrideca-4,6-dien-1-yl,cyclotrideca-4,7-dien-1-yl, cyclotrideca-4,8-dien-1-yl,cyclotrideca-4,9-dien-1-yl, cyclotrideca-4,10-dien-1-yl,cyclotrideca-5,7-dien-1-yl, cyclotrideca-5,8-dien-1-yl,cyclotrideca-5,9-dien-1-yl, cyclotrideca-6,8-dien-1-yl,cyclotrideca-1,3,5-trien-1-yl, cyclotrideca-1,3,6-trien-1-yl,cyclotrideca-1,3,7-trien-1-yl, cyclotrideca-1,3,8-trien-1-yl,cyclotrideca-1,3,9-trien-1-yl, cyclotrideca-1,3,10-trien-1-yl,cyclotrideca-1,3,11-trien-1-yl, cyclotrideca-1,3,12-trien-1-yl,cyclotrideca-1,4,6-trien-1-yl, cyclotrideca-1,4,7-trien-1-yl,cyclotrideca-1,4,8-trien-1-yl, cyclotrideca-1,4,9-trien-1-yl,cyclotrideca-1,4,10-trien-1-yl, cyclotrideca-1,4,11-trien-1-yl,cyclotrideca-1,4,12-trien-1-yl, cyclotrideca-1,5,7-trien-1-yl,cyclotrideca-1,5,8-trien-1-yl, cyclotrideca-1,5,9-trien-1-yl,cyclotrideca-1,5,10-trien-1-yl, cyclotrideca-1,5,11-trien-1-yl,cyclotrideca-1,5,12-trien-1-yl, cyclotrideca-1,6,8-trien-1-yl,cyclotrideca-1,6,9-trien-1-yl,cyclotrideca-cyclotrideca-1,6,11-trien-1-yl,cyclotrideca-1,6,12-trien-1-yl, cyclotrideca-1,7,9-trien-1-yl,cyclotrideca-1,7,10-trien-1-yl, cyclotrideca-1,7,11-tri-en-1-yl,cyclotrideca-1,7,12-trien-1-yl, cyclotrideca-1,8,10-trien-1-yl,cyclotrideca-1,8,11-trien-1-yl, cyclotrideca-1,8,12-trien-1-yl,cyclotrideca-1,9,11-trien-1-yl, cyclotrideca-1,9,12-trien-1-yl,cyclotrideca-1,10,12-trien-1-yl, cyclotrideca-2,4,6-trien-1-yl,cyclotrideca-2,4,7-trien-1-yl, cyclotrideca-2,4,8-trien-1-yl,cyclotrideca-2,4,9-trien-1-yl, cyclotrideca-2,4,10-trien-1-yl,cyclotrideca-2,4,11-trien-1-yl, cyclotrideca-2,4,12-trien-1-yl,cyclotrideca-2,5,7-trien-1-yl, cyclotrideca-2,5,8-trien-1-yl,cyclotri-deca-2,5,9-trien-1-yl, cyclotri-deca-2,5,10-trien-1-yl,cyclotrideca-2,5,11-trien-1-yl, cyclotrideca-2,5,12-trien-1-yl,cyclotrideca-2,6,8-trien-1-yl, cyclotrideca-2,6,9-trien-1-yl,cyclotrideca-2,6,10-trien-1-yl, cyclotrideca-2,6,11-trien-1-yl,cyclotrideca-2,6,12-trien-1-yl, cyclotrideca-2,7,9-trien-1-yl,cyclotrideca-2,7,10-trien-1-yl, cyclotrideca-2,7,11-trien-1-yl,cyclotrideca-2,7,12-trien-1-yl, cyclotrideca-2,8,10-trien-1-yl,cyclotrideca-2,8,11-trien-1-yl, cyclotrideca-2,8,12-trien-1-yl,cyclotrideca-2,9,11-trien-1-yl, cyclotrideca-2,9,12-trien-1-yl,cyclotri-deca-2,10,12-trien-1-yl, cyclotrideca-3,5,7-trien-1-yl,cyclotrideca-3,5,8-trien-1-yl, cyclotrideca-3,5,9-trien-1-yl,cyclotrideca-3,5,10-trien-1-yl, cyclotrideca-3,5,11-trien-1-yl,cyclotrideca-3,6,8-trien-1-yl, cyclotrideca-3,6,9-trien-1-yl,cyclotrideca-3,6,10-trien-1-yl, cyclotrideca-3,6,11-trien-1-yl,cyclotrideca-3,7,9-trien-1-yl, cyclotrideca-3,7,10-trien-1-yl,cyclotrideca-3,7,11-tri-en-1-yl, cyclotrideca-3,8,10-trien-1-yl,cyclotrideca-4,6,8-trien-1-yl, cyclotrideca-4,6,9-trien-1-yl,cyclotrideca-4,6,10-trien-1-yl, cyclotrideca-4,7,9-trien-1-yl,cyclotrideca-4,7,10-trien-1-yl, cyclotrideca-1,3,5,7-tetraen-1-yl,cyclotrideca-1,3,5,8-tetraen-1-yl, cyclotrideca-1,3,5,9-tetraen-1-yl,cyclotrideca-1,3,5,10-tetraen-1-yl, cyclotrideca-1,3,5,11-tetraen-1-yl,cyclotrideca-1,3,5,12-tetraen-1-yl, cyclotrideca-1,3,6,8-tetraen-1-yl,cyclotrideca-1,3,6,9-tetraen-1-yl, cyclotrideca-1,3,6,10-tetraen-1-yl,cyclotrideca-1,3,6,11-tetraen-1-yl, cyclotrideca-1,3,6,12-tetraen-1-yl,cyclotrideca-1,3,7,9-tetraen-1-yl, cyclotrideca-1,3,7,10-tetraen-1-yl,cyclotrideca-1,3,7,11-tetraen-1-yl, cyclotrideca-1,3,7,12-tetraen-1-yl,cyclotrideca-1,3,8,10-tetraen-1-yl, cyclotrideca-1,3,8,11-tetraen-1-yl,cyclotrideca-1,3,8,12-tetraen-1-yl, cyclotrideca-1,3,9,11-tetraen-1-yl,cyclotrideca-1,3,9,12-tetraen-1-yl, cyclotrideca-1,3,10,12-tetraen-1-yl,cyclotrideca-1,4,6,8-tetraen-1-yl, cyclotrideca-1,4,6,9-tetraen-1-yl,cyclotr-ideca-1,4,6,10-tetraen-1-yl, cyclotrideca-1,4,6,11-tetraen-1-yl,cyclotrideca-1,4,6,12-tetraen-1-yl, cyclotrideca-1,4,7,9-tetraen-1-yl,cyclotrideca-1,4,7,10-tetraen-1-yl, cyclotrideca-1,4,7,11-tetraen-1-yl,cyclotrideca-1,4,7,12-tetraen-1-yl, cyclotrideca-1,4,8,10-tetraen-1-yl,cyclotri-deca-1,4,8,11-tetraen-1-yl, cyclotrideca-1,4,8,12-tetraen-1-yl,cyclotrideca-1,4,9,11-tetraen-1-yl, cyclotrideca-1,4,9,12-tetraen-1-yl,cyclotrideca-1,4,10,12-tetraen-1-yl, cyclotrideca-1,5,7,9-tetraen-1-yl,cyclotrideca-1,5,7,10-tetraen-1-yl, cyclotri-deca-1,5,7,11-tetraen-1-yl,cyclotri-deca-1,5,7,12-tetraen-1-yl, cyclotrideca-1,5,8,10-tetraen-1-yl,cyclotrideca-1,5,8,11-tetraen-1-yl, cyclotrideca-1,5,8,12-tetraen-1-yl,cyclotrideca-1,5,9,11-tetraen-1-yl, cyclotrideca-1,5,9,12-tetraen-1-yl,cyclotrideca-1,5,10,12-tetraen-1-yl, cyclotrideca-1,6,8,10-tetraen-1-yl,cyclotri-deca-1,6,8,11-tetraen-1-yl, cyclotrideca-1,6,8,12-tetraen-1-yl,cyclotrideca-1,6,9,11-tetraen-1-yl, cyclotrideca-1,6,9,12-tetraen-1-yl,cyclotrideca-1,6,10,12-tetraen-1-yl, cyclotrideca-1,7,9,11-tetraen-1-yl,cyclotrideca-1,7,9,12-tetraen-1-yl, cyclotrideca-1,7,10,12-tetraen-1-yl,cyclotrideca-1,8,10,12-tetraen-1-yl, cyclotrideca-2,4,6,8-tetraen-1-yl,cyclotrideca-2,4,6,9-tetraen-1-yl, cyclotrideca-2,4,6,10-tetraen-1-yl,cyclotrideca-2,4,6,11-tetraen-1-yl, cyclotrideca-2,4,6,12-tetraen-1-yl,cyclotrideca-2,4,7,9-tetraen-1-yl, cyclotri-deca-2,4,7,10-tetraen-1-yl,cyclotrideca-2,4,7,11-tetraen-1-yl, cyclotrideca-2,4,7,12-tetraen-1-yl,cyclotrideca-2,4,8,10-tetraen-1-yl, cyclotri-deca-2,4,8,11-tetraen-1-yl,cyclotrideca-2,4,8,12-tetraen-1-yl, cyclotrideca-2,4,9,11-tetraen-1-yl,cyclotrideca-2,4,9,12-tetraen-1-yl, cyclotrideca-2,4,10,12-tetraen-1-yl,cyclotrideca-2,5,7,9-tetraen-1-yl, cyclotrideca-2,5,7,10-tetraen-1-yl,cyclotrideca-2,5,7,11-tetraen-1-yl, cyclotrideca-2,5,7,12-tetraen-1-yl,cyclotrideca-2,5,8,10-tetraen-1-yl, cyclotrideca-2,5,8,11-tetraen-1-yl,cyclotrideca-2,5,8,12-tetraen-1-yl, cyclotri-deca-2,5,9,11-tetraen-1-yl,cyclotrideca-2,5,9,12-tetraen-1-yl, cyclotrideca-2,5,10,12-tetraen-1-yl,cyclotrideca-2,6,8,10-tetraen-1-yl, cyclotrideca-2,6,8,11-tetraen-1-yl,cyclotrideca-2,6,8,12-tetraen-1-yl, cyclotrideca-2,6,9,11-tetraen-1-yl,cyclotrideca-2,6,9,12-tetraen-1-yl, cyclotrideca-2,6,10,12-tetraen-1-yl,cyclotrideca-2,7,9,11-tetraen-1-yl, cyclotrideca-2,7,9,12-tetraen-1-yl,cyclotrideca-2,7,10,12-tetraen-1-yl, cyclotri-deca-3,5,7,9-tetraen-1-yl,cyclotrideca-3,5,7,10-tetraen-1-yl, cyclotrideca-3,5,7,11-tetraen-1-yl,cyclotrideca-3,5,8,10-tetraen-1-yl, cyclotri-deca-3,5,8,11-tetraen-1-yl,cyclotrideca-3,5,9,11-tetraen-1-yl, cyclotrideca-3,6,8,10-tetraen-1-yl,cyclotrideca-3,6,8,11-tetraen-1-yl, cyclotrideca-3,7,9,11-tetraen-1-yl,cyclotrideca-1,3,5,7,9-pentaen-1-yl,cyclotrideca-1,3,5,7,10-pentaen-1-yl,cyclotrideca-1,3,5,7,11-pentaen-1-yl,cyclotrideca-1,3,5,7,12-pentaen-1-yl,cyclotrideca-1,3,5,8,10-pentaen-1-yl,cyclotrideca-1,3,5,8,11-pentaen-1-yl,cyclotrideca-1,3,5,8,12-pentaen-1-yl,cyclotrideca-1,3,5,9,11-pentaen-1-yl,cyclotrideca-1,3,5,9,12-pentaen-1-yl,cyclotrideca-1,3,6,8,10-pentaen-1-yl,cyclotrideca-1,3,6,8,11-pentaen-1-yl,cyclotrideca-1,3,6,8,12-pentaen-1-yl,cyclotrideca-1,3,6,9,11-pentaen-1-yl,cyclotrideca-1,3,6,9,12-pentaen-1-yl,cyclotrideca-1,3,7,9,11-pentaen-1-yl,cyclotrideca-1,3,7,9,12-pentaen-1-yl,cyclotrideca-1,4,6,8,10-pentaen-1-yl,cyclotrideca-1,4,6,8,11-pentaen-1-yl,cyclotrideca-1,4,6,8,12-pentaen-1-yl,cyclotrideca-1,4,6,9,11-pentaen-1-yl,cyclotrideca-1,4,6,9,12-pentaen-1-yl,cyclotrideca-1,4,7,9,11-pentaen-1-yl,cyclotrideca-1,4,7,9,12-pentaen-1-yl,cyclotrideca-1,5,7,9,11-pentaen-1-yl,cyclotrideca-1,5,7,9,12-pentaen-1-yl,cyclotrideca-2,4,6,8,10-pentaen-1-yl,cyclotrideca-2,4,6,8,11-pentaen-1-yl,cyclotrideca-2,4,6,8,12-pentaen-1-yl,cyclotrideca-2,4,6,9,11-pentaen-1-yl,cyclotrideca-2,5,7,9,11-pentaen-1-yl,cyclotrideca-2,5,7,9,12-pentaen-1-yl,cyclotrideca-1,3,5,7,9,11-hexaen-1-yl andcyclotrideca-2,4,6,8,10,12-hexaen-1-yl.

The term “C₁₄-cycloalkenyl,” as used herein, meanscyclotetradec-1-en-1-yl, cyclotetradec-2-en-1-yl,cyclotetradec-3-en-1-yl, cyclotetradec-4-en-1-yl,cyclotetradec-5-en-1-yl, cyclotetradec-6-en-1-yl,cyclotetradec-7-en-1-yl, cyclotetradec-8-en-1-yl,cyclotetradeca-1,3-dien-1-yl, cyclotetradeca-1,4-dien-1-yl,cyclotetradeca-1,5-dien-1-yl, cyclotetradeca-1,6-dien-1-yl,cyclotetradeca-1,7-dien-1-yl, cyclotetradeca-1,8-dien-1-yl,cyclotetradeca-1,9-dien-1-yl, cyclotetradeca-1,10-dien-1-yl,cyclotetradeca-1,11-dien-1-yl, cyclotetradeca-1,12-dien-1-yl,cyclotetradeca-1,13-dien-1-yl, cyclotetradeca-2,4-dien-1-yl,cyclotetradeca-2,5-dien-1-yl, cyclotetradeca-2,6-dien-1-yl,cyclotetradeca-2,7-dien-1-yl, cyclotetradeca-2,8-dien-1-yl,cyclotetradeca-2,9-dien-1-yl, cyclotetradeca-2,10-dien-1-yl,cyclotetradeca-2,11-dien-1-yl, cyclotetradeca-2,12-dien-1-yl,cyclotetradeca-2,13-dien-1-yl, cyclotetradeca-3,5-dien-1-yl,cyclotetradeca-3,6-dien-1-yl, cyclotetradeca-3,7-dien-1-yl,cyclotetradeca-3,8-dien-1-yl, cyclotetradeca-3,9-dien-1-yl,cyclotetradeca-3,10-dien-1-yl, cyclotetradeca-3,11-dien-1-yl,cyclotetradeca-3,12-dien-1-yl, cyclotetradeca-4,6-dien-1-yl,cyclotetradeca-4,7-dien-1-yl, cyclotetradeca-4,8-dien-1-yl,cyclotetradeca-4,9-dien-1-yl, cyclotetradeca-4,10-dien-1-yl,cyclotetradeca-4,11-dien-1-yl, cyclotetradeca-5,7-dien-1-yl,cyclotetradeca-5,8-dien-1-yl, cyclotetradeca-5,9-dien-1-yl,cyclotetradeca-5,10-dien-1-yl, cyclotetradeca-6,8-dien-1-yl,cyclotetra-deca-6,9-dien-1-yl, cyclotetradeca-1,3,5-tetraen-1-yl,cyclotetradeca-1;3,6-tetraen-1-yl, cyclotetradeca-1,3,7-tetraen-1-yl,cyclotetradeca-1,3,8-tetraen-1-yl, cyclotetradeca-1,3,9-tetraen-1-yl,cyclotetradeca-1,3,10-tetraen-1-yl, cyclotetradeca-1,3,11-tetraen-1-yl,cyclotetradeca-1,3,12-tetraen-1-yl, cyclotetradeca-1,3,13-tetraen-1-yl,cyclotetradeca-1,4,6-tetraen-1-yl, cyclotetradeca-1,4,7-tetraen-1-yl,cyclotetradeca-1,4,8-tetraen-1-yl, cyclotetradeca-1,4,9-tetraen-1-yl,cyclotetradeca-1,4,10-tetraen-1-yl, cyclotetradeca-1,4,11-tetraen-1-yl,cyclotetradeca-1,4,12-tetraen-1-yl, cyclotetradeca-1,4,13-tetraen-1-yl,cyclotetradeca-1,5,7-tetraen-1-yl, cyclotetradeca-1,5,8-tetraen-1-yl,cyclotetradeca-1,5,9-tetraen-1-yl, cyclotetradeca-1,5,10-tetraen-1-yl,cyclotetradeca-1,5,11-tetraen-1-yl, cyclotetradeca-1,5,12-tetraen-1-yl,cyclotetradeca-1,5,13-tetraen-1-yl, cyclotetradeca-1,6,8-tetraen-1-yl,cyclotetradeca-1,6,9-tetraen-1-yl, cyclotetradeca-1,6,10-tetraen-1-yl,cyclotetradeca-1,6,11-tetraen-1-yl, cyclotetradeca-1,6,12-tetraen-1-yl,'cyclotetradeca-1,6,13-tetraen-1-yl, cyclotetradeca-1,7,9-tetraen-1-yl,cyclotetradeca-1,7,10-tetraen-1-yl, cyclotetradeca-1,7,11-tetraen-1-yl,cyclotetradeca-1,7,12-tetraen-1-yl, cyclotetradeca-1,7,13-tetraen-1-yl,cyclotetradeca-1,8,10-tetraen-1-yl, cyclotetradeca-1,8,11-tetraen-1-yl,cyclotetradeca-1,8,12-tetraen-1-yl, cyclotetradeca-1,8,13-tetraen-1-yl,cyclotetradeca-1,9,11-tetraen-1-yl, cyclotetradeca-1,9,12-tetraen-1-yl,cyclotetradeca-1,9,13-tetraen-1-yl, cyclotetradeca-1,10,12-tetraen-1-yl,cyclotetradeca-1,10,13-tetraen-1-yl,cyclotetradeca-1,11,13-tetraen-1-yl, cyclotetradeca-2,4,6-tetraen-1-yl,cyclotetradeca-2,4,7-tetraen-1-yl, cyclotetradeca-2,4,8-tetraen-1-yl,cyclotetradeca-2,4,9-tetraen-1-yl, cyclotetradeca-2,4,10-tetraen-1-yl,cyclotetradeca-2,4,11-tetraen-1-yl, cyclotetradeca-2,4,12-tetraen-1-yl,cyclotetradeca-2,4,13-tetraen-1-yl, cyclotetradeca-2,5,7-tetraen-1-yl,cyclotetradeca-2,5,8-tetraen-1-yl, cyclotetradeca-2,5,9-tetraen-1-yl,cyclotetradeca-2,5,10-tetraen-1-yl, cyclotetradeca-2,5,11-tetraen-1-yl,cyclotetradeca-2,5,12-tetraen-1-yl, cyclotetradeca-2,5,13-tetraen-1-yl,cyclotetradeca-2,6,8-tetraen-1-yl, cyclotetradeca-2,6,9-tetraen-1-yl,cyclotetradeca-2,6,10-tetraen-1-yl, cyclotetradeca-2,6,11-tetraen-1-yl,cyclotetradeca-2,6,12-tetraen-1-yl, cyclotetradeca-2,6,13-tetraen-1-yl,cyclotetradeca-2,7,9-tetraen-1-yl, cyclotetradeca-2,7,10-tetraen-1-yl,cyclotetradeca-2,7,11-tetraen-1-yl, cyclotetradeca-2,7,12-tetraen-1-yl,cyclotetradeca-2,7,13-tetraen-1-yl, cyclotetradeca-2,8,10-tetraen-1-yl,cyclotetradeca-2,8,11-tetraen-1-yl, cyclotetradeca-2,8,12-tetraen-1-yl,cyclotetradeca-2,8,13-tetraen-1-yl, cyclotetradeca-2,9,11-tetraen-1-yl,cyclotetradeca-2,9,12-tetraen-1-yl, cyclotetradeca-2,9,13-tetraen-1-yl,cyclotetradeca-2,10,12-tetraen-1-yl,cyclotetradeca-2,10,13-tetraen-1-yl,cyclotetradeca-2,11,13-tetraen-1-yl, cyclotetradeca-3,5,7-tetraen-1-yl,cyclotetradeca-3,5,8-tetraen-1-yl, cyclotetradeca-3,5,9-tetraen-1-yl,cyclotetradeca-3,5,10-tetraen-1-yl, cyclotetradeca-3,5,11-tetraen-1-yl,cyclotetradeca-3,5,12-tetraen-1-yl, cyclotetradeca-3,6,8-tetraen-1-yl,cyclotetradeca-3,6,9-tetraen-1-yl, cyclotetradeca-3,6,10-tetraen-1-yl,cyclotetradeca-3,6,11-tetraen-1-yl, cyclotetradeca-3,6,12-tetraen-1-yl,cyclotetradeca-3,7,9-tetraen-1-yl, cyclotetradeca-3,7,10-tetraen-1-yl,cyclotetradeca-3,7,11-tetraen-1-yl, cyclotetradeca-3,7,12-tetraen-1-yl,cyclotetradeca-3,8,10-tetraen-1-yl, cyclotetradeca-3,8,11-tetraen-1-yl,cyclotetradeca-3,9,11-tetraen-1-yl, cyclotetradeca-4,6,8-tetraen-1-yl,cyclotetradeca-4,6,9-tetraen-1-yl, cyclotetradeca-4,6,10-tetraen-1-yl,cyclotetradeca-4,6,11-tetraen-1-yl, cyclotetradeca-4,7,9-tetraen-1-yl,cyclotetradeca-4,7,10-tetraen-1-yl, cyclotetradeca-4,7,11-tetraen-1-yl,cyclotetradeca-4,8,10-tetraen-1-yl, cyclotetradeca-1,3,5,7-tetraen-1-yl,cyclotetradeca-1,3,5,8-tetraen-1-yl,cyclotetradeca-1,3,5,9-tetraen-1-yl,cyclotetradeca-1,3,5,10-tetraen-1-yl,cyclotetradeca-1,3,5,11-tetraen-1-yl,cyclotetradeca-1,3,5,12-tetraen-1-yl,cyclotetradeca-1,3,5,13-tetraen-1-yl,cyclotetradeca-1,3,6,8-tetraen-1-yl,cyclotetradeca-1,3,6,9-tetraen-1-yl,cyclotetradeca-1,3,6,10-tetraen-1-yl,cyclotetradeca-1,3,6,11-tetraen-1-yl,cyclotetradeca-1,3,6,12-tetraen-1-yl,cyclotetradeca-1,3,6,13-tetraen-1-yl,cyclotetradeca-1,3,7,9-tetraen-1-yl,cyclotetradeca-1,3,7,10-tetraen-1-yl,cyclotetradeca-1,3,7,11-tetraen-1-yl,cyclotetradeca-1,3,7,12-tetraen-1-yl,cyclotetradeca-1,3,7,13-tetraen-1-yl,cyclotetradeca-1,3,8,10-tetraen-1-yl,cyclotetradeca-1,3,8,11-tetraen-1-yl,cyclotetradeca-1,3,8,12-tetraen-1-yl,cyclotetradeca-1,3,8,13-tetraen-1-yl,cyclotetradeca-1,3,9,11-tetraen-1-yl,cyclotetradeca-1,3,9,12-tetraen-1-yl,cyclotetradeca-1,3,9,13-tetraen-1-yl,cyclotetradeca-1,3,10,12-tetraen-1-yl,cyclotetradeca-1,3,10,13-tetraen-1-yl,cyclotetradeca-1,3,11,13-tetraen-1-yl,cyclotetradeca-1,4,6,8-tetraen-1-yl,cyclotetradeca-1,4,6,9-tetraen-1-yl,cyclotetradeca-1,4,6,10-tetraen-1-yl,cyclotetradeca-1,4,6,11-tetraen-1-yl,cyclotetradeca-1,4,6,12-tetraen-1-yl,cyclotetradeca-1,4,6,13-tetraen-1-yl,cyclotetradeca-1,4,7,9-tetraen-1-yl,cyclotetradeca-1,4,7,10-tetraen-1-yl,cyclotetradeca-1,4,7,11-tetraen-1-yl,cyclotetradeca-1,4,7,12-tetraen-1-yl,cyclotetradeca-1,4,7,13-tetraen-1-yl,cyclotetradeca-1,4,8,10-tetraen-1-yl,cyclotetradeca-1,4,8,11-tetraen-1-yl,cyclotetradeca-1,4,8,12-tetraen-1-yl,cyclotetradeca-1,4,8,13-tetraen-1-yl,cyclotetradeca-1,4,9,11-tetraen-1-yl,cyclotetradeca-1,4,9,12-tetraen-1-yl,cyclotetradeca-1,4,9,13-tetraen-1-yl,cyclotetradeca-1,4,10,12-tetraen-1-yl,cyclotetradeca-1,4,10,13-tetraen-1-yl,cyclotetradeca-1,4,11,13-tetraen-1-yl,cyclotetradeca-1,5,7,9-tetraen-1-yl,cyclotetradeca-1,5,7,10-tetraen-1-yl,cyclotetradeca-1,5,7,11-tetraen-1-yl,cyclotetradeca-1,5,7,12-tetraen-1-yl,cyclotetradeca-1,5,7,13-tetraen-1-yl,cyclotetradeca-1,5,8,10-tetraen-1-yl,cyclotetradeca-1,5,8,11-tetraen-1-yl,cyclotetradeca-1,5,8,12-tetraen-1-yl,cyclotetradeca-1,5,8,13-tetraen-1-yl,cyclotetradeca-1,5,9,11-tetraen-1-yl,cyclotetradeca-1,5,9,12-tetraen-1-yl,cyclotetradeca-1,5,9,13-tetraen-1-yl,cyclotetradeca-1,5,10,12-tetraen-1-yl,cyclotetradeca-1,5,10,13-tetraen-1-yl,cyclotetradeca-1,5,11,13-tetraen-1-yl,cyclotetradeca-1,6,8,10-tetraen-1-yl,cyclotetradeca-1,6,8,11-tetraen-1-yl,cyclotetradeca-1,6,8,12-tetraen-1-yl,cyclotetradeca-1,6,8,13-tetraen-1-yl,cyclotetradeca-1,6,9,11-tetraen-1-yl,cyclotetradeca-1,6,9,12-tetraen-1-yl,cyclotetradeca-1,6,9,13-tetraen-1-yl,cyclotetradeca-1,6,10,12-tetraen-1-yl,cyclotetradeca-1,6,10,13-tetraen-1-yl,cyclotetradeca-1,6,11,13-tetraen-1-yl,cyclotetradeca-1,7,9,11-tetraen-1-yl,cyclotetradeca-1,7,9,12-tetraen-1-yl,cyclotetradeca-1,7,9,13-tetraen-1-yl,cyclotetradeca-1,7,10,12-tetraen-1-yl,cyclotetradeca-1,7,10,13-tetraen-1-yl,cyclotetradeca-1,7,11,13-tetraen-1-yl,cyclotetradeca-1,8,10,12-tetraen-1-yl,cyclotetradeca-1,8,10,13-tetraen-1-yl,cyclotetradeca-1,8,11,13-tetraen-1-yl,cyclotetradeca-2,4,6,8-tetraen-1-yl,cyclotetradeca-2,4,6,9-tetraen-1-yl,cyclotetradeca-2,4,6,10-tetraen-1-yl,cyclotetradeca-2,4,6,11-tetraen-1-yl,cyclotetradeca-2,4,6,12-tetraen-1-yl,cyclotetradeca-2,4,6,13-tetraen-1-yl,cyclotetradeca-2,4,7,9-tetraen-1-yl,cyclotetradeca-2,4,7,10-tetraen-1-yl,cyclotetradeca-2,4,7,11-tetraen-1-yl,cyclotetradeca-2,4,7,12-tetraen-1-yl,cyclotetradeca-2,4,7,13-tetraen-1-yl,cyclotetradeca-2,4,8,10-tetraen-1-yl,cyclotetradeca-2,4,8,11-tetraen-1-yl,cyclotetradeca-2,4,8,12-tetraen-1-yl,cyclotetradeca-2,4,8,13-tetraen-1-yl,cyclotetradeca-2,4,9,11-tetraen-1-yl,cyclotetradeca-2,4,9,12-tetraen-1-yl,cyclotetradeca-2,4,9,13-tetraen-1-yl,cyclotetradeca-2,4,10,12-tetraen-1-yl,cyclotetradeca-2,4,10,13-tetraen-1-yl,cyclotetradeca-2,4,11,13-tetraen-1-yl,cyclotetradeca-2,5,7,9-tetraen-1-yl,cyclotetradeca-2,5,7,10-tetraen-1-yl,cyclotetradeca-2,5,7,11-tetraen-1-yl,cyclotetradeca-2,5,7,12-tetraen-1-yl,cyclotetradeca-2,5,7,13-tetraen-1-yl,cyclotetradeca-2,5,8,10-tetraen-1-yl,cyclotetradeca-2,5,8,11-tetraen-1-yl,cyclotetradeca-2,5,8,12-tetraen-1-yl,cyclotetradeca-2,5,8,13-tetraen-1-yl,cyclotetradeca-2,5,9,11-tetraen-1-yl,cyclotetradeca-2,5,9,12-tetraen-1-yl,cyclotetradeca-2,5,9,13-tetraen-1-yl,cyclotetradeca-2,5,10,12-tetraen-1-yl,cyclotetradeca-2,5,10,13-tetraen-1-yl,cyclotetradeca-2,6,8,10-tetraen-1-yl,cyclotetradeca-2,6,8,11-tetraen-1-yl,cyclotetradeca-2,6,8,12-tetraen-1-yl,cyclotetradeca-2,6,8,13-tetraen-1-yl,cyclotetradeca-2,6,9,11-tetraen-1-yl,cyclotetradeca-2,6,9,12-tetraen-1-yl,cyclotetradeca-2,6,9,13-tetraen-1-yl,cyclotetradeca-2,6,10,12-tetraen-1-yl,cyclotetradeca-2,6,10,13-tetraen-1-yl,cyclotetradeca-2,6,11,13-tetraen-1-yl,cyclotetradeca-2,7,9,11-tetraen-1-yl,cyclotetradeca-2,7,9,12-tetraen-1-yl,cyclotetradeca-2,7,10,12-tetraen-1-yl,cyclotetradeca-3,5,7,9-tetraen-1-yl,cyclotetradeca-3,5,7,10-tetraen-1-yl,cyclotetradeca-3,5,7,11-tetraen-1-yl,cyclotetradeca-3,5,7,12-tetraen-1-yl,cyclotetradeca-3,5,8,10-tetraen-1-yl,cyclotetradeca-3,5,8,11-tetraen-1-yl,cyclotetradeca-3,5,8,12-tetraen-1-yl,cyclotetradeca-3,5,9,11-tetraen-1-yl,cyclotetradeca-3,5,9,12-tetraen-1-yl,cyclotetradeca-3,5,10,12-tetraen-1-yl,cyclotetradeca-3,6,8,10-tetraen-1-yl,cyclotetradeca-3,6,8,11-tetraen-1-yl,cyclotetradeca-3,6,8,12-tetraen-1-yl,cyclotetradeca-3,7,9,11-tetraen-1-yl,cyclotetradeca-1,3,5,7,9-pentaen-1-yl,cyclotetradeca-1,3,5,7,10-pentaen-1-yl,cyclotetradeca-1,3,5,7,11-pentaen-1-yl,cyclotetradeca-1,3,5,7,12-pentaen-1-yl,cyclotetradeca-1,3,5,7,13-pentaen-1-yl,cyclotetra-deca-1,3,5,8,10-pentaen-1-yl,cyclotetradeca-1,3,5,8,11-pentaen-1-yl,cyclotetradeca-1,3,5,8,12-pentaen-1-yl,cyclotetradeca-1,3,5,8,13-pentaen-1-yl,cyclotetradeca-1,3,5,9,11-pentaen-1-yl,cyclotetradeca-1,3,5,9,12-pentaen-1-yl,cyclotetradeca-1,3,5,9,13-pentaen-1-yl,cyclotetradeca-1,3,5,10,12-pentaen-1-yl,cyclotetradeca-1,3,5,10,13-pentaen-1-yl,cyclotetradeca-1,3,5,11,13-pentaen-1-yl,cyclotetradeca-1,3,6,8,10-pentaen-1-yl,cyclotetradeca-1,3,6,8,11-pentaen-1-yl,cyclotetradeca-1,3,6,8,12-pentaen-1-yl,cyclotetradeca-1,3,6,8,13-pentaen-1-yl,cyclotetradeca-1,3,6,9,11-pentaen-1-yl,cyclotetradeca-1,3,6,9,12-pentaen-1-yl,cyclotetradeca-1,3,6,9,13-pentaen-1-yl,cyclotetradeca-1,3,7,9,11-pentaen-1-yl,cyclotetradeca-1,3,7,9,12-pentaen-1-yl,cyclotetradeca-1,3,7,9,13-pentaen-1-yl,cyclotetradeca-1,4,6,8,10-pentaen-1-yl,cyclotetradeca-1,4,6,8,11-pentaen-1-yl,cyclotetradeca-1,4,6,8,12-pentaen-1-yl,cyclotetradeca-1,4,6,8,13-pentaen-1-yl,cyclotetradeca-1,4,6,9,11-pentaen-1-yl,cyclotetradeca-1,4,6,9,12-pentaen-1-yl,cyclotetradeca-1,4,6,9,13-pentaen-1-yl,cyclotetradeca-1,4,7,9,11-pentaen-1-yl,cyclotetradeca-1,4,7,9,12-pentaen-1-yl,cyclotetradeca-1,4,7,9,13-pentaen-1-yl,cyclotetradeca-1,5,7,9,11-pentaen-1-yl,cyclotetradeca-1,5,7,9,12-pentaen-1-yl,cyclotetradeca-1,5,7,9,13-pentaen-1-yl,cyclotetradeca-2,4,6,8,10-pentaen-1-yl,cyclotetradeca-2,4,6,8,11-pentaen-1-yl,cyclotetradeca-2,4,6,8,12-pentaen-1-yl,cyclotetradeca-2,4,6,8,13-pentaen-1-yl,cyclotetradeca-2,4,6,9,11-pentaen-1-yl,cyclotetradeca-2,4,6,9,12-pentaen-1-yl,cyclotetradeca-2,4,6,9,13-pentaen-1-yl,cyclotetradeca-2,4,6,10,12-pentaen-1-yl,cyclotetradeca-2,4,6,10,13-pentaen-1-yl,cyclotetradeca-2,4,6,11,13-pentaen-1-yl,cyclotetradeca-2,4,7,9,11-pentaen-1-yl,cyclotetradeca-2,4,7,9,12-pentaen-1-yl,cyclotetradeca-2,4,7,9,13-pentaen-1-yl,cyclotetradeca-2,4,7,10,12-pentaen-1-yl,cyclotetradeca-2,4,7,10,13-pentaen-1-yl,cyclotetradeca-2,4,7,11,13-pentaen-1-yl,cyclotetradeca-2,4,8,10,12-pentaen-1-yl,cyclotetradeca-2,4,8,10,13-pentaen-1-yl,cyclotetradeca-2,5,7,9,11-pentaen-1-yl,cyclotetradeca-2,5,7,9,12-pentaen-1-yl,cyclotetradeca-2,5,7,9,13-pentaen-1-yl,cyclotetradeca-2,5,7,10,12-pentaen-1-yl,cyclotetradeca-2,5,7,10,13-pentaen-1-yl,cyclotetradeca-1,3,5,7,9,11-hexaen-1-yl,cyclotetradeca-1,3,5,7,9,12-hexaen-1-yl,cyclotetradeca-1,3,5,7,9,13-hexaen-1-yl,cyclotetradeca-2,4,6,8,10,12-hexaen-1-yl,cyclotetradeca-2,4,6,8,10,13-hexaen-1-yl,cyclotetradeca-2,4,6,8,11,13-hexaen-1-yl andcyclotetradeca-1,3,5,7,9,11,13-heptaen-1-yl.

The term “C₃-cycloalkyl,” as used herein, means cycloprop-1-yl.

The term “C₄-cycloalkyl,” as used herein, means cyclobut-1-yl.

The term “C₅-cycloalkyl,” as used herein, means cyclopent-1-yl.

The term “C₆-cycloalkyl,” as used herein, means cyclohex-1-yl.

The term “C₇-cycloalkyl,” as used herein, means bicyclo[2.2.1]hept-1-yl,bicyclo[2.2.1]hept-2-yl, cyclohept-1-yl, bicyclo[2.2.1]hept-7-yl andcyclohept-1-yl.

The term “C₈-cycloalkyl,” as used herein, means bicyclo[2.2.2]oct-1-yl,bicyclo[2.2.2]oct-2-yl, bicyclo[2.2.2]oct-7-yl, cyclooct-1-yl.

The term “C₈-cycloalkyl,” as used herein, means cyclonon-1-yl.

The term “C₁₀-cycloalkyl,” as used herein, means adamant-1-yl,adamant-2-yl and cyclodec-1-yl. The term “C₁₁-cycloalkyl,” as usedherein, means cycloundec-1-yl, tricyclo[4.3.1.1^(3,8)]undec-1-yl(homoadamant-1-yl), tricyclo[4.3.1.1^(3,8)]undec-2-yl(homoadamant-2-yl), tricyclo[4.3.1.1^(3,8)]undec-3-yl(homoadamant-3-yl), tricyclo[4.3.1.1^(3,8)]undec-4-yl(homoadamant-4-yl), and tricyclo[4.3.1.1^(3,8)]undec-9-yl(homoadamant-9-yl).

The term “C₁₂-cycloalkyl,” as used herein, means cyclododec-1-yl.

The term “C₁₃-cycloalkyl,” as used herein, means cyclotridec-1-yl.

The term “C₁₄-cycloalkyl,” as used herein, means cyclotetradec-1-yl.

The term “C₂-spiroalkenyl,” as used herein, means ethen-1,2-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₃-spiroalkenyl,” as used herein, means prop-1-en-1,3-ylene,both ends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₄-spiroalkenyl,” as used herein, means but-1-en-1,4-ylene,but-2-en-1,4-ylene and buta-1,3-dien-1,4-ylene, both ends of whichreplace hydrogen atoms of the same CH₂ moiety.

The term “C₅-spiroalkenyl,” as used herein, means pent-1-en-1,5-yl-ene,pent-2-en-1,5-ylene, penta-1,3-dien-1,5-ylene andpenta-1,4-dien-1,5-ylene, both ends of which replace hydrogen atoms ofthe same CH₂ moiety.

The term “C₆-spiroalkenyl,” as used herein, means hex-1-en-1,6-ylene,hex-2-en-1,6-ylene, hexa-1,3-dien-1,6-ylene, hexa-1,4-di-en-1,6-yleneand hexa-1,3,5-trien-1,6-ylene, both ends of which replace hydrogenatoms of the same CH₂ moiety.

The term “C₇-spiroalkenyl,” as used herein, means hept-1-en-1,7-yl-ene,hept-2-en-1,7-ylene, hept-3-en-1,7-ylene, hepta-1,3-dien-1,7-ylene,hepta-1,4-dien-1,7-ylene, hepta-1,5-dien-1,7-ylene,hepta-2,4-dien-1,7-ylene, hepta-2,5-dien-1,7-ylene,hepta-1,3,5-trien-1,7-ylene and hepta-1,3,6-trien-1,7-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₈-spiroalkenyl,” as used herein, means oct-1-en-1,8-ylene,oct-2-en-1,8-ylene, oct-3-en-1,8-ylene, octa-1,3-dien-1,8-ylene,octa-1,4-dien-1,8-ylene, octa-1,5-dien-1,8-ylene,octa-1,6-dien-1,8-ylene, octa-2,4-dien-1,8-ylene,octa-2,5-dien-1,8-ylene, octa-3,5-dien-1,8-ylene,octa-1,3,5-trien-1,8-ylene, octa-1,3,6-trien-1,8-ylene andocta-2,4,6-tri-en-1,8-ylene, both ends of which replace hydrogen atomsof the same CH₂ moiety.

The term “C₉-spiroalkenyl,” as used herein, means nona-1-en-1,9-yl-ene,nona-2-en-1,9-ylene, nona-3-en-1,9-ylene, nona-4-en-1,9-ylene,nona-1,3-dien-1,9-ylene, nona-1,4-dien-1,9-ylene,nona-1,5-dien-1,9-ylene, nona-1,6-dien-1,9-ylene,nona-1,7-dien-1,9-ylene, nona-1,8-dien-1,9-ylene,nona-2,4-dien-1,9-ylene, nona-2,5-dien-1,9-ylene,nona-2,6-dien-1,9-ylene, nona-2,7-dien-1,9-ylene,nona-3,5-dien-1,9-ylene, nona-3,6-dien-1,9-ylene,nona-4,6-dien-1,9-ylene, nona-1,3,5-trien-1,9-ylene,nona-1,3,6-trien-1,9-ylene, nona-1,3,7-trien-1,9-ylene,nona-1,3,8-trien-1,9-ylene, nona-1,4,6-trien-1,9-yl-ene,nona-1,4,7-trien-1,9-ylene, nona-1,4,8-trien-1,9-ylene,nona-1,5,7-trien-1,9-ylene, nona-2,4,6-trien-1,9-ylene,nona-2,4,7-trien-1,9-ylene, nona-1,3,5,7-tetraen-1,9-ylene,nona-1,3,5,8-tetraen-1,9-ylene and nona-1,3,6,9-tetraen-1,9-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₂-spiroalkyl,” as used herein, means eth-1,2-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₃-spiroalkyl,” as used herein, means prop-1,3-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₄-spiroalkyl,” as used herein, means but-1,4-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₅-spiroalkyl,” as used herein, means pent-1,5-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₆-spiroalkyl,” as used herein, means hex-1,6-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₇-spiroalkyl,” as used herein, means hept-1,7-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₈-spiroalkyl,” as used herein, means oct-1,8-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₉-spiroalkyl,” as used herein, means non-1,9-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

Compounds of this invention contain asymmetrically substituted carbonatoms in the R or S configuration, in which the terms “R” and “S” are asdefined by the IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds havingasymmetrically substituted carbon atoms with equal amounts of R and Sconfigurations are racemic at those carbon atoms. Atoms with an excessof one configuration over the other are assigned the configurationpresent in the higher amount, preferably an excess of about 85%-90%,more preferably an excess of about 95%-99%, and still more preferably anexcess greater than about 99%. Accordingly, this invention includesracemic mixtures, relative and absolute stereoisomers, and mixtures ofrelative and absolute stereoisomers.

Compounds of this invention may also contain carbon-carbon double bondsor carbon-nitrogen double bonds in the Z or E configuration, in whichthe term “Z” represents the larger two substituents on the same side ofa carbon-carbon or carbon-nitrogen double bond and the term “E”represents the larger two substituents on opposite sides of acarbon-carbon or carbon-nitrogen double bond. The compounds may alsoexist as an equilibrium mixture of Z or E configurations.

Compounds of this invention containing NH, C(O)OH, OH or SH moieties mayhave attached thereto prodrug-forming moieties. The prodrug-formingmoieties are removed by metabolic processes and release the compoundshaving the freed hydroxyl, amino or carboxylic acid in vivo. Prodrugsare useful for adjusting such pharmacokinetic properties of thecompounds as solubility and/or hydrophobicity, absorption in thegastrointestinal tract, bioavailability, tissue penetration, and rate ofclearance.

Metabolites of compounds having formula (I), produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with expression of an anti-apoptotic protein family membersuch as of BCl-X_(L) protein, and Bcl-2 protein or Bcl-w protein.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds having formula (I) may also have utility for treatingdiseases associated with expression of an anti-apoptotic protein familymember such as of BCl-X_(L) protein, and Bcl-2 protein or Bcl-w protein.

Compounds having formula (I) may exist as an acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring their isolation or following their purification. Acid additionsalts of the compounds are those derived from the reaction of thecompounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate,glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate,propionate, succinate, tartrate, thiocyanate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds and prodrugs thereof are contemplated as being embraced bythis invention. Basic addition salts of the compounds are those derivedfrom the reaction of the compounds with the hydroxide, carbonate orbicarbonate of cations such as lithium, sodium, potassium, calcium, andmagnesium.

The compounds having formula (I) may be administered, for example,bucally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperintoneally intrasternally, intravenously,subcutaneously), rectally, topically, transdermally, or vaginally.

Therapeutically effective amounts of compounds having formula (I) dependon recipient of treatment, disorder being treated and severity thereof,composition containing it, time of administration, route ofadministration, duration of treatment, its potency, its rate ofclearance and whether or not another drug is co-administered. The amountof a compound of this invention having formula (I) used to make acomposition to be administered daily to a patient in a single dose or individed doses is from about 0.03 to about 200 mg/kg body weight. Singledose compositions contain these amounts or a combination of submultiplesthereof.

Compounds having formula (I) may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound havingformula (I) to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having formula (I) to be administered ophthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having formula (I) to be administered osmotically include, forexample, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having formula (I) to be administered parenterally include,for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil,dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil,peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil,U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having formula (I) to be administered rectally or vaginallyinclude, for example, cocoa butter, polyethylene glycol, wax andmixtures thereof.

Compounds having formula (I) may also be administered with one or morethan one additional therapeutic agents, wherein additional therapeuticagents include radiation or chemotherapeutic agents, whereinchemotherapeutic agents include, but are not limited to, carboplatin,cisplatin, cyclophosphamide, dacarbazine, dexamethasone, docetaxel,doxorubicin, etoposide, fludarabine, irinotecan, CHOP (C: Cytoxan®(cyclophosphamide); H: Adiamycin® (hydroxydoxorubicin); O: Vincristine(Oncovin®); P: prednisone), paclitaxel, rapamycin, Rituxin® (rituximab)and vincristine.

For determination of the utility of compounds having formula (I) asinhibitors of the activity of anti-apoptotic Bcl-X_(L), representativeexamples in DMSO at concentrations between 100 μM and 1 pM and added toeach well of a 96-well microtiter plate. A mixture totaling 125 μL perwell of assay buffer (20 mM phosphate buffer, pH 7.4), 1 mM EDTA, 50 mMNaCl, 0.05% PF-68), 30 nM Bcl-X_(L) protein (prepared as described inScience 1997, 275, 983-986), 15 nM fluorescein-labeled BAD peptide(prepared in-house), and the DMSO solution of the example was shaken for2 minutes then placed in a LJL Analyst (LJL Bio Systems, Calif.). Anegative control (DMSO, 15 nM BAD peptide, assay buffer) and a positivecontrol (DMSO, 15 nM BAD peptide, 30 nM Bcl-X_(L), assay buffer) wereused to determine the range of the assay. Polarization was measured at25° C. with a continuous Fluorescein lamp (excitation 485 nm; emission530 nm). Percentage of inhibition was determined by (1−((mP value ofwell-negative control)/range))×100%.

IC₅₀ values (concentration of example needed for 50% inhibition ofBcl-X_(L)) for the representative compounds having formula (I),calculated using Microsoft Excel, were 3.7 nM, 5.8 nM, 6.1 nM, 6.2 nM,6.9 nM, 7.1 nM, 7.1 nM, 7.4 nM, 7.7 nM, 7.8 nM, 7.9 nM, 8.3 nM, 8.3 nM,8.3 nM, 8.4 nM, 8.4 nM, 8.5 nM, 8.5 nM, 8.7 nM, 8.8 nM, 9.1 nM, 9.1 nM,9.1 nM, 9.2 nM, 9.5 nM, 9.6 nM, 9.7 nM, 9.8 nM, 9.8 nM, 9.9 nM, 9.9 nM,9.9 nM, 10.0 nM, 10.0 nM, 10.0 nM, 10.0 nM, 10.1 nM, 10.1 nM, 10.2 nM,10.2 nM, 10.3 nM, 10.3 nM, 10.3 nM, 10.3 nM, 10.3 nM, 10.3 nM, 10.3 nM,10.3 nM, 10.5 nM, 10.6 nM, 10.6 nM, 10.6 nM, 10.6 nM, 10.6 nM, 10.7 nM,10.7 nM, 10.7 nM, 10.7 nM, 10.8 nM, 10.8 nM, 10.8 nM, 10.8 nM, 10.9 nM,10.9 nM, 10.9 nM, 10.9 nM, 11.0 nM, 11.0 nM, 11.0 nM, 11.0 nM, 11.0 nM,11.1 nM, 11.1 nM, 11.1 nM, 11.1 nM, 11.1 nM, 11.1 nM, 11.1 nM, 11.1 nM,11.1 nM, 11.2 nM, 11.2 nM, 11.2 nM, 11.2 nM, 11.2 nM, 11.2 nM, 11.2 nM,11.3 nM, 11.3 nM, 11.3 nM, 11.3 nM, 11.4 nM, 11.5 nM, 11.5 nM, 11.5 nM,11.5 nM, 11.5 nM, 11.6 nM, 11.6 nM, 11.6 nM, 11.6 nM, 11.6 nM, 11.6 nM,11.6 nM, 11.7 nM, 11.7 nM, 11.8 nM, 11.8 nM, 11.9 nM, 11.9 nM, 11.9 nM,11.9 nM, 11.9 nM, 12.1 nM, 12.1 nM, 12.1 nM, 12.2 nM, 12.2 nM, 12.3 nM,12.3 nM, 12.3 nM, 12.3 nM, 12.4 nM, 12.4 nM, 12.4 nM, 12.4 nM, 12.5 nM,12.5 nM, 12.5 nM, 12.6 nM, 12.6 nM, 12.6 nM, 12.6 nM, 12.6 nM, 12.7 nM,12.7 nM, 12.7 nM, 12.8 nM, 12.8 nM, 12.8 nM, 12.8 nM, 12.8 nM, 12.8 nM,12.8 nM, 12.8 nM, 12.9 nM, 12.9 nM, 12.9 nM, 12.9 nM, 13.0 nM, 13.0 nM,13.1 nM, 13.2 nM, 13.2 nM, 13.2 nM, 13.3 nM, 13.3 nM, 13.4 nM, 13.4 nM,13.5 nM, 13.5 nM, 13.5 nM, 13.6 nM, 13.6 nM, 13.6 nM, 13.7 nM, 13.7 nM,13.7 nM, 13.7 nM, 13.7 nM, 13.7 nM, 13.8 nM, 13.8 nM, 13.8 nM, 13.8 nM,13.9 nM, 13.9 nM, 13.9 nM, 13.9 nM, 13.9 nM, 13.9 nM, 13.9 nM, 14.0 nM,14.0 nM, 14.0 nM, 14.0 nM, 14.1 nM, 14.1 nM, 14.1 nM, 14.1 nM, 14.2 nM,14.2 nM, 14.2 nM, 14.3 nM, 14.3 nM, 14.4 nM, 14.4 nM, 14.4 nM, 14.5 nM,14.6 nM, 14.6 nM, 14.7 nM, 14.7 nM, 14.7 nM, 14.7 nM, 14.7 nM, 14.7 nM,14.7 nM, 14.7 nM, 14.8 nM, 14.8 nM, 14.8 nM, 14.9 nM, 14.9 nM, 14.9 nM,14.9 nM, 14.9 nM, 15.0 nM, 15.0 nM, 15.1 nM, 15.1 nM, 15.2 nM, 15.2 nM,15.3 nM, 15.3 nM, 15.3 nM, 15.4 nM, 15.4 nM, 15.5 nM, 15.5 nM, 15.5 nM,15.5 nM, 15.6 nM, 15.6 nM, 15.7 nM, 15.8 nM, 15.9 nM, 15.9 nM, 15.9 nM,15.9 nM, 15.9 nM, 15.9 nM, 16.0 nM, 16.0 nM, 16.0 nM, 16.0 nM, 16.0 nM,16.1 nM, 16.1 nM, 16.1 nM, 16.1 nM, 16.1 nM, 16.2 nM, 16.2 nM, 16.4 nM,16.4 nM, 16.4 nM, 16.4 nM, 16.4 nM, 16.5 nM, 16.5 nM, 16.5 nM, 16.6 nM,16.6 nM, 16.7 nM, 16.8 nM, 16.8 nM, 16.9 nM, 17.0 nM, 17.0 nM, 17.0 nM,17.1 nM, 17.1 nM, 17.2 nM, 17.2 nM, 17.3 nM, 17.3 nM, 17.3 nM, 17.4 nM,17.4 nM, 17.4 nM, 17.5 nM, 17.5 nM, 17.6 nM, 17.8 nM, 17.8 nM, 17.8 nM,17.8 nM, 17.9 nM, 17.9 nM, 18.1 nM, 18.2 nM, 18.2 nM, 18.2 nM, 18.3 nM,18.4 nM, 18.4 nM, 18.8 nM, 18.8 nM, 18.8 nM, 18.9 nM, 18.9 nM, 19.1 nM,19.2 nM, 19.2 nM, 19.3 nM, 19.3 nM, 19.4 nM, 19.4 nM, 19.6 nM, 19.7 nM,19.7 nM, 19.8 nM, 19.8 nM, 19.9 nM, 20.0 nM, 20.2 nM, 20.3 nM, 20.3 nM,20.3 nM, 20.3 nM, 20.7 nM, 20.7 nM, 20.7 nM, 20.8 nM, 20.9 nM, 21.4 nM,21.5 nM, 21.7 nM, 21.9 nM, 22.0 nM, 22.2 nM, 22.3 nM, 22.5 nM, 22.6 nM,22.9 nM, 23.2 nM, 23.3 nM, 23.5 nM, 23.8 nM, 23.8 nM, 24.4 nM, 24.5 nM,25.0 nM, 25.2 nM, 25.6 nM, 25.7 nM, 25.8 nM, 25.9 nM, 26.1 nM, 26.4 nM,26.4 nM, 26.7 nM, 27.7 nM, 27.9 nM, 28.3 nM, 28.4 nM, 28.9 nM, 29.5 nM,29.6 nM, 29.7 nM, 29.9 nM, 30.3 nM, 30.5 nM, 30.9 nM, 31.0 nM, 31.1 nM,31.3 nM, 31.8 nM, 32.1 nM, 32.2 nM, 32.4 nM, 33.2 nM, 33.4 nM, 33.7 nM,37.1 nM, 39.3 nM, 39.5 nM, 40.8 nM, 42.1 nM, 44.6 nM, 44.6 nM, 44.9 nM,44.9 nM, 45.2 nM, 47.4 nM, 47.5 nM, 51.5 nM, 51.6 nM, 53.2 nM, 55.6 nM,56.0 nM, 58.3 nM, 58.7 nM, 58.9 nM, 61.0 nM, 65.7 nM, 68.3 nM, 83.6 nM,85.9 nM, 0.2 μM, 0.2 μM, 0.2 μM, 0.2 μM, 0.2 μM, 0.2 μM, 0.3 μM, 0.2 μM,0.2 μM, 0.3 μM, 0.3 μM, 0.3 μM, 0.5 μM, 0.5 μM, 0.9 μM, 1.0 μM, 1.0 μM,1.0 μM, 1.1 μM, 1.2 μM, 1.4 μM, 1.5 μM, 1.5 μM, 1.9 μM, 2.0 μM, 2.1 μM,2.1 μM, 2.7 μM, 2.7 μM, 2.9 μM, 3.1 μM, 3.4 μM, 3.6 μM, 3.6 μM, 3.7 μM,5.5 μM, 5.5 μM, 6.6 μM, 6.8 μM, 7.8 μM, 10.0 μM, 10.0 μM, 10.0 μM, 10.0μM, 10.0 μM, 10.0 μM and 13.5 μM.

Determination of the utility of compounds having formula (I) asinhibitiors of anti-apoptotic Bcl-2 was also performed in 96-wellmicrotiter plates. Representative examples were diluted in DMSO toconcentrations between 10 pM and 10 pM and added to each well of theplate. A mixture totaling 125 μL per well of assay buffer (20 mMphosphate buffer, pH 7.4), 1 mM EDTA, 50 mM NaCl, 0.05% PF-68), 10 nMBcl-2 protein (prepared as described in PNAS 2001, 98, 3012-3017), 1 nMfluorescein-labeled BAX peptide (prepared in-house), and the DMSOsolution of the example was shaken for 2 minutes and placed in the LJLAnalyst. Polarization was measured at 25° C. using a continuousFluorescein lamp (excitation 485nm; emission 530nm).

K_(i) values for the representative compounds having formula (I),calculated using Microsoft Excel, were <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, <1.0 nM, 1.1 nM, 1.1nM, 1.1 nM, 1.1 nM, 1.1 nM, 1.1 nM, 1.1 nM, 1.1 nM, 1.2 nM, 1.2 nM, 1.3nM, 1.3 nM, 1.3 nM, 1.3 nM, 1.3 nM, 1.4 nM, 1.5 nM, 1.5 nM, 1.5 nM, 1.5nM, 1.6 nM, 1.6 nM, 1.7 nM, 1.7 nM, 1.7 nM, 1.7 nM, 1.8 nM, 1.8 nM, 1.8nM, 1.8 nM, 1.9 nM, 2.0 nM, 2.0 nM, 2.2 nM, 2.3 nM, 2.4 nM, 2.5 nM, 2.5nM, 2.6 nM, 2.6 nM, 2.9 nM, 3.0 nM, 3.1 nM, 3.5 nM, 3.7 nM, 3.9 nM, 4.0nM, 4.0 nM, 4.0 nM, 4.2 nM, 4.4 nM, 4.5 nM, 4.6 nM, 4.7 nM, 5.8 nM, 5.9nM, 6.0 nM, 6.2 nM, 6.5 nM; 6.7 nM, 7.0 nM, 7.2 nM, 7.7 nM, 7.8 nM, 8.0nM, 8.1 nM, 8.4 nM, 9.4 nM, 10.4 nM, 10.4 nM, 13.1 nM, 13.6 nM, 13.8 nM,15.2 nM, 15.7 nM, 15.9 nM, 16.2 nM, 16.9 nM, 19.7 nM, 22.5 nM, 24.4 nM,25.4 nM, 26.9 nM, 28.9 nM, 29.1 nM, 32.4 nM, 33.0 nM, 36.5 nM, 38.0 nM,39.7 nM, 41.7 nM, 42.9 nM, 45.7 nM, 53.9 nM, 56.2 nM, 56.6 nM, 62.3 nM,71.6 nM, 72.9 nM, 80.4 nM, 82.4 nM, 83.4 nM, 0.09 μM, 0.09 μM, 1.0 μM,0.12 μM, 0.12 μM, 0.15 μM, 0.30 μM, 0.001 μM, 0.001 μM, 0.001 μM, 0.001μM, 0.001 μM, 0.002 μM, 0.002 μM, 0.003 μM, 0.685 μM, 1.011 μM, 0.004μM, 0.054 μM, 1.051 μM, 10.0 μM, 0.011 μM, 0.046 μM and 0.014 μM.

These binding and inhibitory data demonstrate the utility of compoundshaving formula (I) as inhibitors of anti-apopotic BCl-X_(L) protein andanti-apopotic Bcl-2.

It is expected that, because compounds having formula (I) bind to andinhibit the activity of BCl-X_(L) and Bcl-2, they would also haveutility as inhibitors of anti-apopotic protein family members havingclose structural homology to BCl-X_(L) and Bcl-2, such as, for example,anti-apopotic Bcl-w protein.

Accordingly, compounds having formula (I) are expected. to have utilityin treatment of diseases during which anti-apopotic Bcl-X_(L) protein,anti-apopotic Bcl-2 protein, anti-apopotic Bcl-w protein or acombination thereof, are expressed.

Diseases during which anti-apopotic protein family members such asBCl-X_(L) protein, Bcl-2 protein and Bcl-w protein are expressed includecancer and autoimmune disorders, wherein cancer includes, but is notlimited to, bladder cancer, brain cancer, breast cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer and small cell lung cancer (CancerRes., 2000, 60, 6101-10); autoimmune disorders include, but are notlimited to, acquired immunodeficiency disease syndrome, autoimmunelymphoproliferative syndrome, hemolytic anemia, inflammatory diseases,and thrombocytopenia (Current Allergy and Asthma Reports 2003,3:378-384; Br. J. Haematol. 2000 September; 110(3): 584-90; Blood 2000Feb. 15; 95(4):1283-92; and New England Journal of Medicine 2004September; 351(14): 1409-1418).

A representative compound having formula (I), EXAMPLE 2, displayedtherapeutic utility against human tumor cell lines derived from smallcell lung carcinomas and lymphoid malignancies of both T-cell and B-cellorigin.

EXAMPLE 2 also displayed therapeutic utility against acutelymphoblastoid leukemia, small cell lung cancer, prostate cancer,non-small cell lung cancer, and follicular lymphoma tumors (RS11380,DoHH2 and SuDHL-4) in xenograft models.

EXAMPLE 2 also demonstrated anti-tumor activity in two murine models(H146 and SCLC xenograft) from human-derived small cell lung cancerisolated from smokers and nonsmokers, defective for Rb/p53 genefunction, and expresseive of moderately high levels of Bcl-2. In theH146 model, treatment with EXAMPLE 2 resulted in complete regression ofan established tumor with, in some cases, tumor disappearance afterprolonged therapy.

EXAMPLE 2 also prolonged survival in a systemic model of acutelymphoblastic leukemia and inhibited tumor growth in a model offollicular lymphoma (DOHH-2). Therapeutic utility was also observed in aprostate cancer model.

Without being limited by theory, the genetic link between Bcl-2 andcancer comes from the observation that t(14;18) chromosomaltranslocations in B-cell lymphomas lead to overexpression of theprotein. Aberrant Bcl-2 and Bcl-X_(L) expression is also seen in otherlymphoid malignancies such as chronic lymphocytic leukemia and acutelymphocytic leukemia. EXAMPLE 2 exhibited significant activity in aCCRF-CEM T-cell acute lymphoblastoid leukemia model as well as in SuDHL4and RS11380, two models of B-cell follicular lymphoma.

CCRF-CEM is a p53-mutant acute lympoblastoid leukemia line of T-cellorigin used as an animal (mouse) model of systemic leukemia involvingintravenous inoculation of tumor cells. If left untreated, the micesuccumb to disease within about 34 days post inoculation, at which timeextensive tumor infiltration of spleen, liver, and bone marrow hasoccurred. Administration of EXAMPLE 2 increased the average survival ofthe mice and showed significant decrease in average spleen weightrelative to vehicle controls (indicative of a lower tumor burden in thisorgan). Subsequent histopahtological assessments revealed lower tumorinfiltration in both the liver and spleen relative to controls.

The therapeutic effect of EXAMPLE 2 on other human tumor cell lines isshown in TABLE 1 for which the EC₅₀'s are the effective concentrationswhich cause a 50% reduction in cell viability.

TABLE 1 Cell Line^(a) Tumor Type EC₅₀ (uM)^(b) Calu-6 Non-Small CellLung 0.18 ± 0.07 (6) NCI-H460 Non-Small Cell Lung 2.3 ± 1.5 (6) NCI-H226Non-Small Cell Lung 2.6 ± 1.1 (2) NCI-H322M Non-Small Cell Lung 4.1 ±0.8 (2) A549/ATCC Non-Small Cell Lung 5.2 ± 0.2 (2) HOP-62 Non-SmallCell Lung 6.3 ± 6.7 (2) NCI-H23 Non-Small Cell Lung 7.4 ± 0.6 (2) COLO205 Colorectal 0.51 ± 0.07 (4) HCT-15 Colorectal 0.60 ± 0.34 (4) HCT-15Colorectal >11 (2) SW-620 Colorectal 0.69 ± 0.07 (2) DLD-1 Colorectal0.99 ± 0.45 (4) HT-29 Colorectal 1.1 ± 1.1 (6) KM12 Colorectal 1.7 ± 0.2(2) HCT-116 Colorectal 2.1 ± 1.8 (6) MCF7 Breast 2.0 ± 0.8 (2)MDA-MB-435 Breast  2.4 (1) MDA-MB-436 Breast 3.9 ± 2.6 (2) BT-549 Breast6.5 ± 2.3 (2) HS-578T Breast 7.2 ± 8.2 (2) T47D Breast >10 (2)NCI/ADR-RES Breast >10 (2) U251 CNS 3.8 ± 2.0 (2) SF-539 CNS 4.1 ± 0.6(2) SF-295 CNS 7.7 ± 2.3 (2) SF-268 CNS 8.3 ± 0.4 (2) U87MG Glioma 2.7 ±1.8 (2) D54MG Glioma 3.1 ± 2.5 (2) LOX IMVI Melanoma 1.7 ± 0.4 (2)MALME-3M Melanoma 1.9 ± 0.8 (2) SK-MEL-5 Melanoma 3.7 ± 0.8 (2)SK-MEL-28 Melanoma 9.3 ± 0.1 (2) OVCAR-5 Ovarian 1.1 ± 0 (2)   IGROV-1Ovarian 1.7 ± 0.6 (2) OVCAR-3 Ovarian 1.9 ± 0.3 (2) OVCAR-8 Ovarian 3.4± 0.8 (2) SK-OV-3 Ovarian 5.6 ± 1.0 (2) OVCAR-4 Ovarian 22 ± 3 (2) MiaPaCa Pancreas 1.4 ± 0.6 (2) PC3 Prostate 0.96 ± 0.38 (4) DU-145Prostate 8.2 ± 1.1 (2) ACHN Renal  1 (1) 786-0 Renal 2.9 ± 0.1 (2)RXF-393 Renal 2.9 ± 0.4 (2) SN12C Renal 3.2 ± 0.2 (2) ^(a)Serum-freeconditions, 48 hour treatment. ^(b)Mean ± SEM(n).

The therapeutic effect of paclitaxel on A549 human non-small cell lungcarcinoma cells was about 4.4-fold more efficacious when administeredwith EXAMPLE 2. A similar increase (4.7-fold) in efficacy wasdemonstrated against PC-3 prostate carcinoma cells. The enantiomer ofEXAMPLE 2 was less efficacious, indicating that the therapeutic effectof EXAMPLE 2 was the direct result of binding to anti-apoptotic Bcl-2family proteins. The anti-tumor activity of EXAMPLE 2 was equivalent toslightly better than paclitaxel near the maximum tolerated dose in asmall cell lung cancer xenograft tumor model and superior to cisplatinand etoposide. In a PC3 derived murine model of prostate cancer, EXAMPLE2 exhibited about 40-50% inhibition of tumor growth rate.

Studies pertaining to the efficacy of EXAMPLE 2 in combination withetoposide, vincristine, modified CHOP, doxorubicin, rapamycin andRituxin® demonstrated that EXAMPLE 2 synergistically enhanced efficacyof these cytotoxic agents during combination therapy. In particular,combinations comprising EXAMPLE 2 and rapamycin and EXAMPLE 2 andRituxin® resulted in complete regression of a significant percentage ofestablished DoHH2 follicular lymphoma flank tumors for a sustainedperiod of time.

These data demonstrate the utility of compounds having formula (I) fortreatment of diseases which are caused or exascerbated by expression ofone or more than one of an anti-apoptotic protein family member.Furthermore, experiments with representative Bcl-X_(L)-selectivecompounds demonstrated synergistic therapeutic effects with multiplechemotherapeutic agents against cell lines representative of diversetumor types. Accordingly, the compounds having formula (I) are expectedto be useful as chemotherapeutic agents alone or in combination withadditional therapeutic agents.

Compounds having formula (I) may be made by synthetic chemicalprocesses, examples of which are shown herein. It is meant to beunderstood that the order of the steps in the processes may be varied,reagents, solvents, and reaction conditions may be substituted for thosespecifically mentioned, and vulnerable moieties may be protected anddeprotected, as necessary, by NH, C(O)OH, OH, SH protecting groups.

The following abbreviations have the meanings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄); 9-BBN means9-borabicyclo[3.3.1]nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)-butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane; EDAC.HCl means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc meansfluorenylmethoxycarbonyl; HATU meansO-(7-azabenzotriazol-1-yl)-N,N′N′N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporus triethylammoniummethylpolystyrene cyanoborohydride; TEA means triethylamine; TFA meanstrifluoroacetic acid; THF means tetrahydrofuran; NCS meansN-chlorosuccinimide; NMM means N-methylmorpholine; NMP meansN-methylpyrrolidine; PPh₃ means triphenylphosphine.

The term “NH protecting group,” as used herein, meanstrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl,dichloroacetyl, trichioroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenylmethyl, 2-nitrophenylthio, methanesulfonyl,para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclohexylidene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl,naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl,para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl,benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl,succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl,1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group,” as used herein, meansbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichioroacetyl, trifluoroacetyl, methoxyacetyl-phenoxyacetyl, pivaloyl,benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds having formula (1) may be converted to compounds havingformula (2) by reacting the former, chlorosulfonic acid, and ammonia.

Compounds having formula (2) may be converted to compounds havingformula (I) by reacting the former and compounds having formula Z¹—CO₂Hand a coupling agent, with or without a first base. Examples of couplingagents include EDCI, CDI, and PyBop. Examples of first bases includeTEA, DIEA, DMAP, and mixtures thereof.

Compounds having formula (2) may be converted to compounds havingformula (I) by reacting the former and compounds having formula Z¹—COCland the first base.

Compounds having formula (4) may be converted to compounds havingformula (I), wherein B¹ and Y¹ together are imidazole, by reacting theformer, sodium nitrite, hydrochloric acid, and acetic acid. Compoundshaving formula (I), wherein B¹ and Y¹ together are imidazole, may bereacted with a second base and the appropriate electrophile to providecompounds having formula (I), wherein B¹ and Y¹ together are substitutedimidazole. Examples of second bases include sodium hydride, potassiumhydride, lithium diisopropylamide and sodium bis(trimethylsilyl)amide.

Compounds having formula (3), may be converted to compounds havingformula (4) by reacting the former, hydrogen and a hydrogenationcatalyst. Examples of hydrogenation catalysts include Pd on carbon,platinum on carbon, and Raney nickel.

Compounds having formula (4) may be converted to compounds havingformula (I), wherein B¹ and Y¹ together are triazole, by reacting theformer, sodium nitrite, hydrochloric acid, and acetic acid. Compoundshaving formula (I), wherein B¹ and Y¹ together are triazole, may bereacted with the second base and the appropriate electrophile to providecompounds having formula (I), wherein B¹ and Y¹ together are substitutedtriazole.

EXAMPLE 1A

A mixture of piperazine (129.2 g), ethyl-4-fluorobenzoate (84 g), andK₂CO₃ (103.65 g) in DMSO (200 mL) at 120° C. was stirred for 6 hours,poured into water, stirred for 30 minutes, and filtered.

EXAMPLE 1B

EXAMPLE 1A (200 mg) in dioxane at 40° C. (4 mL) was treated with2-(bromomethyl)-1,1′-biphenyl (232 mg) and DIEA (165 mg) andconcentrated. The concentrate was flash chromatographed on silica gelwith 20% ethyl acetate/hexanes.

EXAMPLE 1C

EXAMPLE 1B (340 mg) in 3:1:1 THF/methanol/water (4 mL) at 25° C. wastreated with LiOH.water (143 mg), stirred for 16 hours, and treated with4M HCl (850 μL) and dichloromethane. The extract was dried (Na₂SO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel with 20% methanol/dichloromethane.

EXAMPLE 1D

EXAMPLE 10 (112 mg) in dichloromethane (2.5 mL) at 25° C. was treatedwith4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in commonly-owned International Application No.PCT/US01/29432, published as WO 02/24636, (115 mg), EDAC.HCl (109 mg),and DMAP (49 mg), stirred for 16 hours, and concentrated. Theconcentrate was flash chromatographed on silica gel with 20%methanol/dichloromethane. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.28(d, 1H), 7.78 (dd, 1H), 7.72 (d, 2H), 7.54 (dd, 1H), 7.45-7.41 (m, 4H),7.40-7.28 (m, 6H), 7.25 (td, 2H), 7.17 (tt, 1H), 6.88 (d, 1H), 6.78 (d,2H), 4.10-4.01 (m, 1H), 3.41 (s, 2H), 3.33 (d, 2H), 3.14 (m, 4H),2.82-2.62 (m, 2H), 2.44-2.35 (m, 10H), 2.09-1.91 (m, 2H).

EXAMPLE 1E

EXAMPLE 1C (112 mg) in dichloromethane (2.5 mL) at 25° C. was treatedwith EXAMPLE 1D (115 mg), EDAC.HCl (109 mg), and DMAP (49 mg), stirredfor 16 hours, and concentrated. The concentrate was flashchromatographed on silica gel with 20% methanol/dichloromethane. ¹H NMR(300 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.28 (d, 1H), 7.78 (dd, 1H), 7.72 (d,2H), 7.54 (dd, 1H), 7.45-7.41 (m, 4H), 7.40-7.28 (m, 6H), 7.25 (td, 2H),7.17 (tt, 1H), 6.88 (d, 1H), 6.78 (d, 2H), 4.10-4.01 (m, 1H), 3.41 (s,2H), 3.33 (d, 2H), 3.14 (m, 4H), 2.82-2.62 (m, 2H), 2.44-2.35 (m, 10H),2.09-1.91 (m, 2H).

EXAMPLE 2A

A mixture of EXAMPLE 1A (23.43 g), 2-bromobenzyl bromide (26.24 g), andDIEA (20.94 mL) in acetonitrile (200 mL) at 25° C. was stirred for 2hours and filtered.

EXAMPLE 2B

A mixture of EXAMPLE 2A (13.83 g), 4-chlorophenyl-boronic acid (7.04 g),bis(triphenylphosphine)palladium dichloride (481 mg) and 2M sodiumcarbonate (22.5 mL) in 7:3:2 DME/water/ethanol (200 mL) at 90° C. wasstirred for 4.5 hours and extracted with ethyl acetate. The extract wasdried (MgSO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 5%-40% ethyl acetate/hexanes.

EXAMPLE 2C

A mixture of EXAMPLE 2B (13 g) and lithium hydroxide hydrate (3.78 g) indioxane (250 mL) and water (100 mL) at 95° C. was stirred for 16 hoursand concentrated. The concentrate in water was heated at 80° C. andfiltered. The filtrate was treated with 1M HCl (90 mL) and filtered.

EXAMPLE 2D

A mixture of EXAMPLE 2C (3.683 g),4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide(3.53 g), EDAC.HCl (3.32 g) and DMAP (2.12 g) in dichloromethane (500mL) at 25° C. was stirred for 8 hours, washed with saturated NH₄Cl (330mL), and dried (MgSO₄), filtered, and concentrated. The concentrate wasflash chromatographed on silica gel with 1%, 2%, 5%, 10%, and 15%methanol/NH₃-saturated dichloromethane. ¹H NMR (DMSO-d₆) δ 12.10 (br s,1H), 11.18 (br s, 1H), 10.40 (br s, 1H), 8.54 (s, 1H), 8.29 (d, 1H),8.10 (br s, 1H), 7.85 (d, 1H), 7.77 (d, 2H), 7.52 (d, 4H), 7.40-7.36 (m,2H), 7.35-7.32 (m, 1H), 7.26-7.21 (m, 2H), 7.16-7.09 (m, 3H), 6.93 (d,2H), 4.34 (br s, 2H), 4.35-4.23 (m, 1H), 3.88 (br s, 2H), 3.42-3.36 (m,4H), 3.17-3.07 (m, 2H), 2.90-2.78 (m, 2H), 2.50 (s, 6H), 2.20-2.15 (m,2H).

EXAMPLE 3A

This example was prepared by substituting 4-methoxyphenylboronic acidfor 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 3B

This example was prepared by substituting EXAMPLE 3A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 3C

This example was prepared by substituting EXAMPLE 3B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 9.9 (br s,1H), 9.57 (s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77 (d,2H), 7.72 (m, 1H), 7.50 (m, 2H), 7.33 (m, 1H), 7.29 (d, 2H), 7.23 (dd,2H), 7.18 (d, 1H), 7.11 (m, 2H), 7.03 (d, 2H), 6.93 (d, 3H), 4.36 (br s,2H), 4.18 (m, 1H), 3.80 (br s, 2H), 3.79 (s, 3H), 3.39 (d, 2H), 3.07 (m,6H), 2.75 (s, 3H), 2.74 (s, 3H), 2.14 (q, 2H).

EXAMPLE 4A

This example was prepared by substituting 4-fluorophenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 4B

This example was prepared by substituting EXAMPLE 4A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 4C

This example was prepared by substituting EXAMPLE 4B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 10.00 (br s,1H), 9.65 (s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77 (d,2H), 7.74 (m, 1H), 7.52 (m, 2H), 7.41 (m, 2H), 7.34 (m, 1H), 7.29 (t,2H), 7.23 (dd, 2H), 7.18 (d, 1H), 7.12 (m, 3H), 6.93 (d, 2H), 4.29 (brs, 4H), 4.19 (m, 1H), 3.84 (br s, 2H), 3.39 (d, 2H), 3.13 (m, 4H), 2.92(m, 2H), 2.74 (s, 6H), 2.15 (m, 2H).

EXAMPLE 5A

This example was prepared by substituting4-(methylsulfanyl)phenylboronic acid for 4-chlorophenylboronic acid inEXAMPLE 2B.

EXAMPLE 5B

This example was prepared by substituting EXAMPLE 5A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 5C

This example was prepared by substituting EXAMPLE 5B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H), 9.9 (br s, 1H),9.54 (s, 1H), 8.53 (d, 1H), 8.27 (d, 1H), 7.85 (dd, 1H), 7.76 (d, 2H),7.72 (m, 1H), 7.51 (dd, 2H), 7.33 (d, 2H), 7.31 (m, 1H), 7.29 (d, 2H),7.21 (d, 2H), 7.16 (d, 1H), 7.10 (m, 3H), 6.92 (d, 2H), 4.32 (br s, 2H),4.17 (m, 1H), 3.85 (br s, 4H), 3.38 (d, 2H), 3.11 (m, 5H), 2.90 (br s,1H), 2.73 (s, 6H), 2.49 (s, 3H), 2.14 (m, 2H).

EXAMPLE 6A

This example was prepared by substituting 1,1′-biphenyl-4-ylboronic acidfor 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 6B

This example was prepared by substituting EXAMPLE 6A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 6C

This example was prepared by substituting EXAMPLE 6B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 9.9 (br s,1H), 9.56 (s, 1H), 8.54 (d, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.75 (m,7H), 7.56 (m, 2H), 7.48 (m, 4H), 7.39 (m, 2H), 7.22 (dd, 2H), 7.17 (d,1H), 7.11 (m, 3H), 6.93 (d, 2H), 4.42 (br s, 2H), 4.18 (m, 1H), 3.83 (brs, 2H), 3.39 (d, 2H), 3.25 (br s, 2H), 3.13 (m, 4H), 2.91 (m, 2H), 2.74(s, 6H), 2.14 (m, 2H).

EXAMPLE 7A

This example was prepared by substituting 4-phenoxyphenylboronic acidfor 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 7B

This example was prepared by substituting EXAMPLE 7A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 7C

This example was prepared by substituting EXAMPLE 7B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 10.10 (br s,1H), 9.64 (s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.78 (d,2H), 7.73 (m, 1H), 7.51 (m, 2H), 7.38 (m, 5H), 7.23 (m, 2H), 7.14 (m,5H), 7.07 (d, 4H), 6.95 (d, 2H), 4.33 (br s, 2H), 4.20 (m, 1H), 3.86 (brs, 2H), 3.39 (d, 2H), 3.25 (br s, 2H), 3.12 (m, 4H), 2.92 (m, 2H), 2.74(s, 6H), 2.15 (m, 2H).

EXAMPLE 8

This example was prepared by substituting4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz,

DMSO-d₆) δ 12.05 (br s, 1H), 9.8 (br s, 1H), 8.53 (s, 1H), 8.51 (d, 1H),7.83 (dd, 1H), 7.79 (d, 2H), 7.72 (br s, 1H), 7.52 (br s, 2H), 7.47 (t,2H), 7.41 (t, 1H), 7.36 (d, 2H), 7.35 (m, 2H), 7.26 (d, 2H), 7.01 (t,2H), 6.93 (d, 2H), 6.92 (d, 1H), 4.32 (br s, 2H), 3.79 (br s, 2H), 3.49(br s, 4H), 3,14 (br s, 2H), 2.80 (br s, 2H), 1.56 (s, 6H).

EXAMPLE 9

This example was prepared by substituting4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.60 (d, 1H), 8.40 (d, 1H),7.89 (dd, 1H), 7.79 (d, 2H), 7.64 (m, 7H), 7.62 (d, 1H), 7.31 (d, 2H),7.30 (d, 1H), 7.24 (dd, 2H), 7.19 (dd, 2H), 6.94 (d, 2H), 4.24 (m, 1H),3.71 (m, 4H), 3.55 (m, 2H), 3.41 (d, 2H), 3.31 (m, 4H), 2.80 (m, 4H),2.48 (m, 4H),'2.16 (m, 1H), 2.06 (m, 1H).

EXAMPLE 10

This example was prepared by substituting3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide), preparedas described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 11.87 (br s, 1H), 8.74 (t,1H), 8.58 (d, 1H), 7.89 (dd, 1H), 7.72 (d, 2H), 7.55 (m, 1H), 7.38 (m,7H), 7.26 (m, 4H), 7.17 (m, 2H), 6.89 (d, 3H), 3.66 (m, 2H), 3.47 (m,2H), 3.26 (m, 6H), 2.41 (m, 4H).

EXAMPLE 11

This example was prepared by substituting3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.93 (s, 1H), 8.66 (t, 1H),8.56 (d, 1H), 7.89 (dd, 1H), 7.73 (d, 2H), 7.51 (d, 1H), 7.47 (m, 4H),7.37 (m, 4H), 7.28 (t, 2H), 7.24 (m, 1H), 7.18 (t, 1H), 7.11 (d, 1H),6.86 (d, 2H), 3.64 (q, 2H), 3.40 (s, 2H), 3.27 (q, 2H), 3.21 (m, 4H),2.40 (m, 4H).

EXAMPLE 12

This example was prepared by substituting4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.07 (s, 1H), 9.98 (s, 2H),8.55 (d, 1H), 8.30 (d, 1H), 7.87 (dd, 1H), 7.77 (d, 2H), 7.72 (br s,1H), 7.52 (d, 4H), 7.40 (d, 2H), 7.34 (m, 1H), 7.23 (d, 2H), 7.18 (d,1H), 7.15 (t, 2H), 7.10 (m, 1H), 6.93 (d, 2H), 4.25 (br s, 2H), 4.19 (m,1H), 3.95 (br s, 5H), 3.63 (br s, 4H), 3.40 (m, 4H), 3.18 (m, 4H), 3.02(br s, 3H), 2.18 (m, 2H).

EXAMPLE 13

This example was prepared by substituting4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene-sulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.06 (br s, 1H), 9.69 (br s,1H),.8.53 (s, 1H), 8.51 (d, 1H), 7.83 (dd, 1H), 7.80 (d, 2H), 7.71 (brs, 1H), 7.52 (d, 4H), 7.40 (d, 2H), 7.37 (d, 1H), 7.33 (m, 1H), 7.26 (d,2H), 7.01 (t, 2H), 6.93 (m, 3H), 4.33 (br s, 2H), 3.73 (br s, 4H), 3.12(br s, 4H), 2.85 (br s, 2H), 1.56 (s, 6H).

EXAMPLE 14

This example was prepared by substituting4-(((1R)-4-(dimethylamino)-1-((phenylsulfanyl)methyl)butyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-((('1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene-sulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 9.75 (br s,1H), 9.26 (s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.77 (d,2H), 7.74 (m, 1H), 7.52 (d, 4H), 7.39 (d, 2H), 7.34 (m, 1H), 7.23 (m,3H), 7.11 (m, 3H), 6.93 (d, 2H), 4.30 (br s, 2H), 4.14 (m, 1H), 3.73 (brs, 6H), 3.37 (m, 2H), 3.02 (m, 4H), 2.72 (t, 6H), 1.77 (m, 4H).

EXAMPLE 15

This example was prepared by substituting4-(((1R)-5-(dimethylamino)-1-((phenylsulfanyl)methyl)pentyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (s, 1H), 10.96 (m, 1H),9.99 (m, 1H), 8.52 (d, 1H), 8.32 (d, 1H), 8.05 (m, 1H), 7.85 (dd, 1H),7.75 (d, 2H), 7.53 (m, 4H), 7.36 (m, 4H), 7.23 (d, 2H), 7.11 (m, 3H),6.93 (d, 2H), 4.35 (m, 1H), 4.12 (m, 1H), 3.92-3.87 (m, 2H), 3.53 (m,8H), 3.27 (m, 2H), 2.94 (m 2H), 2.69 (s, 3H), 2.68 (s, 3H), 1.76 (m,2H), 1.62 (m, 2H), 1.36 (m, 2H).

EXAMPLE 16

This example was prepared by substituting4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, and EXAMPLE 4B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ12.09 (br s, 1H), 9.93 (br s, 2H), 8.55 (d, 1H), 8.30 (d, 1H), 7.87 (dd,1H), 7.77 (d, 2H), 7.73 (br s, 1H), 7.52 (m, 2H), 7.41 (m, 2H), 7.34 (m,1H), 7.29 (t, 2H), 7.23 (m, 2H), 7.18 (d, 1H), 7.12 (m, 3H), 6.93 (d,2H), 4.28 (br s, 2H), 4.21 (m, 1H), 3.95 (br s, 5H), 3.63 (br s, 4H),3.40 (m, 4H), 3.19 (m, 4H), 3.02 (br s, 3H), 2.18 (m, 2H).

EXAMPLE 17A

A mixture of EXAMPLE 1A (703 mg), 2-bromo-5-fluorobenzaldehyde (914 mg),2.47 mmol/g MP-BH₃CN (4.05 g), and acetic acid (340 μL) in 1:1methanol/dichloromethane (30 mL) was shaken for 1 day and filtered. Thefiltrate was concentrated, and the concentrate was flash chromatographedon silica gel with 5-50% ethyl acetate/hexanes.

EXAMPLE 17B

This example was prepared by substituting EXAMPLE 17A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 17C

This example was prepared by substituting EXAMPLE 17B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 17D

This example was prepared by substituting EXAMPLE 17C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 9.61 (br s,1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.60 (bd,1H), 7.52 (d, 2H), 7.37 (m, 4H), 7.23 (m, 2H), 7.18 (d, 1H), 7.12 (m,3H), 6.94 (d, 2H), 4.18 (m, 3H), 3.80 (br s, 4H), 3.39 (d, 2H), 3.14 (m,3H), 2.89 (s, 3H), 2.75 (s, 6H), 2.15 (m, 2H).

EXAMPLE 18A

3-(R)-((carbobenzyloxy)amino)-γ-butyrolactone, prepared as described inJ. Am. Chem. Soc. 1986, 108, 4943-4952, (7.72 g) in THF (100 mL) at 25°C. was saturated with dimethylamine, stirred for 16 hours, andconcentrated. The concentrate was filtered through a silica gel plugwith 50% acetone/hexanes.

EXAMPLE 18B

EXAMPLE 18A (8.45 g) in toluene (15 mL) at 25° C. was treated withtributylphosphine (9.76 mL) and diphenyldisulfide (7.3 g), heated to 80°C. for 16 hours and concentrated. The concentrate was flashchromatographed on silica gel with 0-50% ethyl acetate/hexanes.

EXAMPLE 18C

EXAMPLE 18B (10.60 g) in 30% HBr/acetic acid (50 mL) at 25° C. wasstirred for 18 hours, concentrated, treated with water (200 mL) and 5%HCl (100 mL), washed with diethyl ether, adjusted to pH 8-9 with Na₂CO₃,and extracted with dichloromethane. The extract was dried (MgSO₄),filtered, and concentrated.

EXAMPLE 18D

1-fluoro-2-(trifluoromethyl)benzene (15 g) in chlorosulfonic acid (50mL) and 1,2-dichloroethane (50 mL) at 70° C. was stirred to for 2 hours,and concentrated. The concentrate in THF (200 mL) at to 0° C. wastreated with concentrated ammonium hydroxide (20 mL), stirred for 10minutes, and poured into ethyl diethyl ether (500 mL). The extract waswashed with brine and dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 30% ethylacetate/hexanes.

EXAMPLE 18E

A mixture of EXAMPLE 18D (1.7 g) and EXAMPLE 18C (1.67 g) in DMSO (17mL) was treated with DIEA (1.22 mL), heated at 110° C. for 24 hours,poured into ethyl acetate (400 mL), washed with water and brine, anddried (Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 50% ethyl acetate/hexanes.

EXAMPLE 18F

EXAMPLE 18E (2.5 g) in THF (20 mL) at 25° C. was treated with 1Mborane.THF (22 mL), stirred for 24 hours, treated with methanol andconcentrated. The concentrate in methanol (20 mL) was treated withHCl-saturated methanol (75 mL), stirred at reflux for 24 hours,concentrated, poured into 1M NaOH, and extracted with ethyl acetate. Theextract was washed with brine and dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 0-5% TEA/ethyl acetate.

EXAMPLE 18G

This example was prepared by substituting EXAMPLE 18F for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 7.94 (d, 1H), 7.80 (dd, 1H),7.73 (d, 2H), 7.53 (dd, 1H), 7.47 (AB q, 4H), 7.41-7.33 (m, 5H), 7.36(dd, 2H), 7.32 (d, 2H), 7.27 (m, 4H), 7.19 (dd, 1H), 6.89 (d, 2H), 6.87(d, 1H), 5.94 (d, 1H), 3.94 (m, 1H), 3.42 (m, 2H), 3.26 (m, 4H), 3.10(m, 1H), 2.96 (m, 1H), 2.67 (s, 6H), 2.41 (m, 4H), 2.13 (m, 2H).

EXAMPLE 19A

3-(R)-((carbobenzyloxy)amino)-γ-butyrolactone, prepared as described inJ. Am. Chem. Soc. 1986, 108, 4943-4952, (62 g) in dioxane (700 mL) wastreated with morpholine (46 mL), heated to 65° C. for 24 hours, cooledand concentrated. The concentrate was flash chromatographed on silicagel with 10% methanol in ethyl acetate.

EXAMPLE 19B

This example was prepared by substituting EXAMPLE 19A for EXAMPLE 18A inEXAMPLE 18B.

EXAMPLE 19C

This example was prepared by substituting EXAMPLE 19B for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 19D

EXAMPLE 19C (45.4 g) in THF (500 mL) at 55° C. was treated with 1Mborane.THF in THF (650 mL), stirred for 24 hours, cooled to 0° C.,treated with methanol, poured into methanol, and concentrated. Theconcentrate in methanol (400 mL) was treated with saturated HCl inmethanol (800 mL), refluxed for 24 hours, concentrated, poured into 2MNaOH, and extracted with ethyl acetate. The extract was washed with 1MNaOH and brine and dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with ethyl acetate,10% methanol/ethyl acetate, and 10% methanol/10% acetonitrile/5% TEA/75%ethyl acetate.

EXAMPLE 19E

This example was prepared by substituting EXAMPLE 19D for EXAMPLE 18C inEXAMPLE 18E.

EXAMPLE 19F

This example was prepared by substituting EXAMPLE 19E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (d, 1H), 7.76 (dd, 1H),7.72 (d, 2H), 7.50 (dd, 1H), 7.47 (s, 4H), 7.41-7.33 (m, 5H), 7.30 (d,2H), 7.24 (dd, 1H), 7.19 (dd, 1H), 6.88 (d, 2H), 6.79 (d, 1H), 5.98 (d,1H), 3.94 (m, 1H), 3.51 (m, 4H), 3.31-3.23 (m, 8H), 2.43 (m, 2H), 2.39(m, 4H), 2.28 (m, 2H), 1.96 (m, 1H), 1.83 (m, 1H).

EXAMPLE 20A

3-(R)-((carbobenzyloxy)amino)-γ-butyrolactone, prepared as described inJ. Am. Chem. Soc. 1986, 108, 4943-4952, (1.8 g) in THF (20 mL) at 25° C.was treated with pyrrolidine (3 mL), stirred for 3 days, andconcentrated with a toluene azeotrope.

EXAMPLE 20B

This example was prepared by substituting EXAMPLE 20A for EXAMPLE 18A inEXAMPLE 18B.

EXAMPLE 20C

This example was prepared by substituting EXAMPLE 20B for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 20D

EXAMPLE 20C (1.8 g) in DMF (30 mL) at 25° C. was treated with TEA (950μL) and 4-fluoro-3-nitrobenzenesulfonamide, prepared as described in WO02/24636, (1.5 g), heated at 60° C. for 150 minutes, poured into water,and extracted with ethyl acetate. The extract was washed with water andbrine and dried (Na₂SO₄), filtered, concentrated. The concentrate wasflash chromatographed on silica gel with 50% ethyl acetate/hexanes.

EXAMPLE 20E

EXAMPLE 20D (2.35 g) in THF (30 mL) at 25° C. was treated with 1Mborane.THF in THF (20 mL), stirred for 24 hours, cooled to 0° C.,treated with methanol, poured into 6M

HCl, stirred for 24 hours, cooled to 0° C., brought to pH 12 with KOH,and extracted with ethyl acetate. The extract was washed with brine anddried (Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with ethyl acetate, 10% methanol/ethylacetate, and 10% methanol/5% TEA/85% ethyl acetate.

EXAMPLE 20F

This example was prepared by substituting EXAMPLE 20E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (br s, 1H), 9.73 (br s,2H), 8.54 (d, ¹H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.77 (d, 2H), 7.74 (m,1H), 7.52 (m, 4H), 7.39 (d, 2H), 7.34 (m, 1H), 7.23 (m, 2H), 7.18 (d,1H), 7.12 (m, 3H), 6.92 (d, 2H), 4.22 (m, 3H), 3.86 (s, 4H), 3.51 (m,2H), 3.38 (m, 2H), 3.21 (m, 4H), 2.94 (m, 4H), 2.15 (m, 2H), 2.00 (m,2H), 1.84 (m, 2H).

EXAMPLE 21

2-Amino-2-methyl-1-propanol (5 g) in dichloromethane (200 mL) at 0° C.was treated with di-tert-butyldicarbonate (3.5 g) stirred for 8 hours at25° C., washed with water, 5% aqueous citric acid, saturated NaHCO₃, andbrine, and dried (MgSO₄), filtered, and concentrated.

EXAMPLE 21B

A mixture of EXAMPLE 21A (980 mg), 2-mercaptothiazole (610 mg), andtriphenylphosphine (1.5 g) in THF (12 mL) at 25° C. was stirred for 20minutes, cooled to 0° C., treated with diisopropylazodicarboxylate (1.1mL) in THF (6 mL), stirred at 25° C. for 3 days, treated with ethylacetate, washed with water and brine, and dried (MgSO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 2%-10% ethyl acetate/hexanes.

EXAMPLE 21C

EXAMPLE 21B (410 mg) in diethyl ether (5 mL) at 25° C. was treated with4M HCl in 1,4-dioxane (5 mL), stirred for 2.5 hours, and filtered.

EXAMPLE 21D

A mixture of EXAMPLE 21C (300 mg) and 4-fluoro-3-nitrobenzenesulfonamide(300 mg), and DIEA (690 μL) in DMSO (2 mL) at 25° C. was stirred for 18hours, cooled to 15° C., treated with water (25 mL), acidified with 1MHCl, cooled to 0° C., stirred for 1 hour, and filtered.

EXAMPLE 21E

This example was prepared by substituting EXAMPLE 21D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (d, 1H), 8.49, (s, 1H),7.90 (dd, 1H), 7.80 (d, 2H), 7.77 (s, 1H), 7.52 (d, 3H), 7.48 (d, 2H),7.45 (dd, 2H), 7.40 (d, 2H), 7.40 (d, 1H), 6.93 (d, 2H), 4.24 (s, 2H),3.86, (s, 2H), 3.35 (m, 6H), 2.85 (s, 2H), 1.58 (s, 6H).

EXAMPLE 22A

A mixture of 2-mercaptothiazole (4.6 g) and tetra-n-butylammoniumpersulfate, prepared as described in Tetrahedron Lett. 1993, 34,3581-3584, (14.7 g) in water (460 mL) at 25° C. was stirred for 18 hoursand extracted with diethyl ether. The extract was washed with brine anddried (MgSO4), filtered, and concentrated.

EXAMPLE 22B

A mixture of EXAMPLE 18A (720 mg) and EXAMPLE 22A (770 mg) in toluene(9.1 mL) at 85° C. was treated with tributylphosphine (830 μL), heatedto 85° C., stirred for 5.5 hours, treated with ethyl acetate, washedwith water and brine, and dried (MgSO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 30%-66% ethylacetate/hexanes.

EXAMPLE 22C

This example was prepared by substituting EXAMPLE 22B for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 22D

This example was prepared by substituting EXAMPLE 22C for EXAMPLE 19C inEXAMPLE 19D.

EXAMPLE 22E

This example was prepared by substituting EXAMPLE 22D for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 22F

This example was prepared by substituting EXAMPLE 22E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.50 (d, 1H), 8.22 (d, 1H),7.90 (dd, 1H), 7.72 (dd, 2H), 7.61 (d, 1H), 7.51 (m, 2H), 7.47 (s, 3H),7.37 (m, 2H), 7.23, (m, 2H), 6.79 (d, 2H), 4.28 (m, 1H), 3.60 (m, 2H),3.39 (s, 2H), 3.14 (m, 4H), 3.00 (m, 2H), 2.62 (s, 6H), 2.40 (m, 4H),2.10 (m, 2H).

EXAMPLE 23A

This example was prepared by substituting 2-thienyldisulfide and THF forEXAMPLE 22A and toluene, respectively, in EXAMPLE 22B.

EXAMPLE 23B

This example was prepared by substituting EXAMPLE 23A for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 23C

This example was prepared by substituting EXAMPLE 23B for EXAMPLE 19C inEXAMPLE 19D.

EXAMPLE 23D

This example was prepared by substituting EXAMPLE 23C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 23E

This example was prepared by substituting EXAMPLE 23D for4-(((1R)-3-(dimethylamino)-3-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.50 (d, 1H), 8.22 (d, 1H),7.90 (dd, 1H), 7.82, (dd, 1H), 7.72 (d, 2H), 7.62 (dd, 1H), 7.51 (m,1H), 7.47 (s, 3H), 7.37 (m, 2H), 7.25 (dd, 1H), 7.14 (dd, 1H), 7.02 (dd,1H), 6.80 (m, 3H), 3.99 (m, 1H), 3.31 (m, 2H), 3.18 (m, 6H), 2.95 (m,3H), 2.59 (s, 6H), 2.40 (t, 3H), 2.11 (m, 1H), 2.02 (m, 1H).

EXAMPLE 24A

N-tert-butoxycarbonyl-L-serine methyl ester (30 g) in dichloromethane(300 mL) at 0° C. was treated with DIEA (59.7 mL) andmethanesulfonylchloride (11.65 mL), stirred for 20 minutes, treated withthiophenol (15.5 mL), stirred at 25° C. for 24 hours, and concentrated.The concentrate was flash chromatographed on silica gel with 10-30%ethyl acetate/hexanes.

EXAMPLE 24B

EXAMPLE 24A (8.35 g) in dichloromethane (75 mL) was treated with 1MDIBAL in dichloromethane (94 mL) stirred for 2 hours, treated withmethanol, poured into saturated NaH₂PO₄ (300 mL), stirred for 30minutes, and extracted with ethyl acetate. The extract was washed withbrine and dried (Na₂SO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 50% ethyl acetate/hexanes.

EXAMPLE 24C

60% Oily NaH (480 mg) in dioxane (30 mL) at 25° C. was treated withEXAMPLE 24B (1.7 g) in dioxane (10 mL), stirred for 10 minutes, treatedwith N,N-dimethylchloroacetamide (1.23 mL), heated at 70° C. for 24hours, poured into water, and extracted with ethyl acetate. The extractwas washed with brine and dried (Na₂SO₄), filtered, and concentrated.The concentrate was flash chromatographed on silica gel with 50% ethylacetate/hexanes.

EXAMPLE 24D

EXAMPLE 24C (1.65 g) in THF (10 mL) at 25° C. was treated with 1Mborane.THF (20 mL), stirred for 24 hours, treated with 5M HCl (300 mL)and THF (300 mL), stirred for 2 days, cooled to 0° C., adjusted to pH 12with KOH and extracted with ethyl acetate. The extract was washed withbrine and dried (Na₂SO₄), filtered, and concentrated. The concentrate inDMF (30 mL) was treated with 4-fluoro-3-nitrobenzenesulfonamide (1 g)and TEA (627 μL), heated at 55° C. for 90 minutes, poured into water,and extracted with ethyl acetate. The extract was washed with water andbrine and dried (Na₂SO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with ethyl acetate, 10%methanol/ethyl acetate, and 10% methano1/10% acetonitrile/80% ethylacetate.

EXAMPLE 24E

This example was prepared by substituting EXAMPLE 24D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (s, 1H), 10.90 (m, 1H),9.90 (m, 1H), 8.56 (d, 1H), 8.52 (d, 1H), 8.04 (m, 1H), 7.86 (dd, 1H),7.76 (d, 2H), 7.53 (m, 4H), 7.13-7.39 (m, 9H), 6.93 (d, 2H), 4.35 (m,1H), 3.87-3.79 (m, 2H), 3.74 (m, 4H), 3.47 (m, 8H), 3.23 (m, 4H), 2.75(m, 6H).

EXAMPLE 25A

Diethylamine (4.15 mL) in THF (150 mL) at −78° C. was treated with 2.5Mn-butyllithium in hexanes (15.4 mL), stirred for 5 minutes at 0° C.,cooled to −78° C., treated with(2R,4S)-3-((benzyloxy)carbonyl)-4-methyl-2-phenyl-1,3-oxazolidin-5-one,prepared as described in Helv. Chim. Acta 1991, 74, 800, (10 g) in THF(40 mL), stirred for 20 minutes, treated with allyl bromide (4.29 mL),stirred for 1 hour, stirred at 25° C. for 18 hours, poured into pH 7buffer, and extracted with diethyl ether. The extract was washed withbrine and dried (Na₂SO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 20% ethyl acetate/hexanes.

EXAMPLE 25B

EXAMPLE 25A (8.18 g) in methanol (200 mL) and water (20 mL) at 25° C.was treated with LiOH.water (1.95 g), stirred for 30 minutes, pouredinto saturated NaH₂PO₄ (200 mL), and extracted with ethyl acetate. Theextract was washed with 1M NaOH and brine and dried (Na₂SO₄), filtered,and concentrated. The base wash was acidified with 12M HCl and extractedwith ethyl acetate. The extract was concentrated, and the concentrate in1:1 ethyl acetate/methanol (50 mL) at 25° C. was treated with 2M(trimethylsilyl)diazomethane in THF (5 mL), stirred for 10 minutes, andconcentrated. The concentrates were combined and flash chromatographedon silica gel with 10% ethyl acetate/hexanes.

EXAMPLE 25C

EXAMPLE 25B (5.03 g) in THF (75 mL) at 25° C. was treated with 1MLiBH(CH₂CH₃)₃ in THF (38 mL), stirred for 2 hours, treated with methanol(30 mL), poured into water, and extracted with ethyl acetate. Theextract was washed with brine and dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 30% ethyl acetate/hexanes.

EXAMPLE 25D

This example was prepared by substituting EXAMPLE 25C for EXAMPLE 18A inEXAMPLE 18B.

EXAMPLE 25E

EXAMPLE 25D (2.9 g) in diethyl ether (45 mL) and tert-butanol (45 mL) at25° C. was treated with AD-mix-β (12.74 g), stirred for 18 hours, pouredinto saturated Na₂CO₃, and extracted with ethyl acetate. The extract waswashed with brine and dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 20-50% ethylacetate/hexanes. The product in THF (30 mL) and water (30 mL) at 25° C.was treated with NaIO₄ (2.75 g), stirred for 20 minutes, poured intowater, and extracted with ethyl acetate. The extract was washed withbrine and dried (Na₂SO₄), filtered, and concentrated.

EXAMPLE 25F

EXAMPLE 25E (1.92 g) in dichloromethane (30 mL) at 25° C. was treatedwith dimethylamine hydrochloride (684 mg), sodium triacetoxyborohydride(1.9 g), and TEA (1.56 mL), stirred for 24 hours, treated with methanoland water, and concentrated. The concentrate was flash chromatographedon silica gel with 50% ethyl acetate/hexanes.

EXAMPLE 25G

This example was prepared by substituting EXAMPLE 25F for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 25H

A mixture of EXAMPLE 25G (600 mg) and4-fluoro-3-nitrobenzene-sulfonamide (554 mg) in DMSO (7 mL) at 25° C.was treated with TEA (351 μL), heated at 60° C. for 90 minutes, pouredinto water (30 mL), and extracted with ethyl acetate. The extract waswashed with water and brine and dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 0-10% methanol/ethyl acetate.

EXAMPLE 25I

This example was prepared by substituting EXAMPLE 25H for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.14 (s, 1H), 10.90 (m, 1H),10.22 (m, 1H), 8.50 (d, 1H), 8.32 (s,1H), 8.04 (m, 1H), 7.83 (m, 3H),7.54 (m, 4H), 7.36 (m, 4H), 7.23 (d, 2H), 6.98-6.85 (m, 5H), 4.35 (m,2H), 3.92-3.87 (m, 2H), 3.74 (m, 2H), 3.48 (m, 8H), 3.23 (m, 2H), 2.70(m, 6H), 1.56 (s, 3H).

EXAMPLE 26A

This example was prepared by substituting methylamine for dimethylaminein EXAMPLE 18A.

EXAMPLE 26B

This example was prepared by substituting EXAMPLE 26A for EXAMPLE 18A inEXAMPLE 18B.

EXAMPLE 26C

This example was prepared by substituting EXAMPLE 26B for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 26D

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 26E

This example was prepared by substituting EXAMPLE 26D for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 26F

EXAMPLE 26E (1.12 g) in THF (7 mL) and acetonitrile (7 mL) at 25° C. wastreated with di-tert-butyldicarbonate (572 mg) and TEA (276 mg), stirredfor 16 hours, and concentrated. The concentrate was flashchromatographed on silica gel with 50% ethyl acetate/hexanes.

EXAMPLE 26G

This example was prepared by substituting EXAMPLE 26F for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 26H

EXAMPLE 26G was flash chromatographed on silica gel withdichloromethane, 1:1 dichloromethane/ethyl acetate, and 10% (7M NH₃ inmethanol) in methanol. A mixture of the free base in dichloromethane at25° C. was treated with 1:1 2M HCl/diethyl ether (10 mL), stirred for 18hours and concentrated. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (s, 1H), 10.94(m, 1H), 8.71 (m, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 8.05 (m, 1H), 7.86(dd, 1H), 7.77 (d, 2H), 7.53 (m, 4H), 7.37 (m, 4H), 7.23 (m, 2H), 7.11(m, 3H), 6.93 (d, 2H), 4.34 (m, 1H), 4.28 (m, 1H), 4.12 (m, 1H),3.92-3.87 (m, 2H), 3.39 (m, 8H), 3.27 (m, 3H), 2.94 (m, 3H), 2.11 (m,2H).

EXAMPLE 27A

A mixture of Fmoc-D-Asp(O-tert-butyl) —OH (10.25 g) and

NMM (2.8 mL) in DME (30 mL) at −15° C. was treated with isobutylchloroformate (4.1 mL), stirred for 10 minutes, and filtered. Thefiltrate was cooled to 0° C., treated with NaBH₄ (2.84 g) in water (15mL), stirred for 5 minutes, treated with water, stirred at 25° C. for 3hours, and filtered.

EXAMPLE 27B

A mixture of EXAMPLE 27A (9.5 g), diphenyl disulfide (7.86 g) andtributylphosphine (7.28 g) in toluene (200 mL) at 80° C. was stirred for5 hours and concentrated. The concentrate was flash chromatographed onsilica gel with 5% to 20% ethyl acetate/hexanes.

EXAMPLE 27C

This example was prepared by substituting EXAMPLE 27B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 27D

This example was prepared by substituting EXAMPLE 27C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 27E

EXAMPLE 27D (1 g) in dichloromethane (5 mL) at 25° C. was treated withTFA (5 mL), stirred for 3 hours, and concentrated. ¹H NMR (500 MHz,DMSO-d₆) δ 8.57 (d, 1H), 8.52 (d, 1H), 7.84 (dd, 1H), 7.75 (d, 2H),7.55-7.35 (m, 7H), 7.27-7.11 (m, 6H), 6.91 (d, 2H), 4.39 (m, 1H), 3.39(2, 2H), 3.31 (s, 8H), 3.26 (m, 2H), 2.81 (d, 2H).

EXAMPLE 28

A mixture of EXAMPLE 27E (160 mg) and N-methyl-morpholine (27 μL) in DMF(1 mL) at 25° C. was treated with HATU (92 mg) and isopropylamine (50μL), stirred for 5 hours, treated with ethyl acetate (200 mL), washedwith 1% HCl, saturated NaHCO₃, water, and brine, and dried (Na₂SO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel with dichloromethane, (1:1) dichloromethane/ethyl acetate,and 5% methanol/dichloromethane. ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (d,1H), 8.52 (d, 1H), 7.93 (d, 1H), 7.83 (dd, 1H), 7.76 (d, 2H), 7.52 (m,2H), 7.38 (m, 3H), 7.23′ (m, 2H), 7.18-7.10 (m, 6H), 6.92 (d, 2H), 4.39(m, 1H), 3.75 (m, 1H), 3.40 (m, 10H), 3.34 (m, 2H), 2.54 (m, 2H), 0.98(d, 3H), 0.91 (d, 3H).

EXAMPLE 29A

EXAMPLE 27B (500 mg) in dichloromethane (3 mL) at 25° C. was treatedwith TFA (3 mL), stirred for 3 hours, and concentrated with adichloromethane azeotrope.

EXAMPLE 29B

A mixture of EXAMPLE 29A (450 mg) and NMM (140 μL) in DMF (3 mL) at 25°C. was treated with HATU (464 mg) and diisopropylamine (283 μL), stirredfor 5 hours, treated with ethyl acetate, washed with 1% HCl, saturatedNaHCO₃, water, and brine, and dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith dichloromethane, 1:1 dichloromethane/ethyl acetate, 5%methanol/dichloromethane.

EXAMPLE 29C

EXAMPLE 29B (200 mg) in THF (5 mL) at 25° C. was treated with 2Mborane.THF in THF (1 mL), stirred for 4 hours, treated with methanol (3mL) and concentrated HCl (1 mL), stirred for 2 hours, brought to pH 7with saturated NaHCO₃, and extracted with dichloromethane. The extractwas washed with water and brine and dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith dichloromethane and 5% methanol/dichloromethane.

EXAMPLE 29D

This example was prepared by substituting EXAMPLE 29C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 29E

This example was prepared by substituting EXAMPLE 29D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.88 (s, 1H), 11.33 (s, 1H),10.13 (s, 1H), 9.57 (s, 1H), 8.30 (d, 1H), 8.08 (d, 1H), 7.94 (m, 1H),7.63 (dd, 1H), 7.55 (d, 2H), 7.30 (m, 4H), 7.15 (m, 2H), 7.09 (m, 1H),6.99 (m, 3H), 6.89 (m, 3H), 6.71 (d, 2H), 4.11 (m, 1H), 3.61 (m, 8H),3.19 (m, 1H), 3.17 (m, 2H), 2.94 (m, 1H), 2.77 (m, 4H), 2.62 (m, 1H),2.05 (m, 1H), 1.53 (m, 2H), 1.09-0.75 (m, 12H).

EXAMPLE 30A

EXAMPLE 27C (2.2 g) in dichloromethane (25 mL) at 0° C. was treated withTFA (25 mL) and water (2.5 mL), stirred at 25° C. for 2 hours, andconcentrated with a toluene azeotrope.

EXAMPLE 30B

EXAMPLE 30A (1 g) in DME (25 mL) at 25° C. was treated with NMM (280μL), cooled to −10° C., treated with isobutyl chloroformate (330 μL),stirred for 15 minutes, treated with sodium borohydride (277 mg) inwater (10 mL), stirred for 45 minutes, and concentrated. The concentratewas treated with 0.5M HCl and extracted with ethyl acetate. The extractwas washed with brine and dried (Na₂SO₄), filtered, and concentrated.The concentrate was flash chromatographed on silica gel with 2%methanol/dichloromethane and 4% methanol/dichloromethane.

EXAMPLE 30C

A mixture of EXAMPLE 30B (705 mg) and TEA (740 μL) in dichloromethane (8mL) at 0° C. was treated with SO₃.pyridine (850 mg) in DMSO (6 mL),stirred at 25° C. for 30 minutes, treated 10% (w/v) aqueous citric acid,and extracted with ethyl acetate. The extract was washed with brine anddried (Na₂SO₄), filtered, and concentrated.

EXAMPLE 30D

EXAMPLE 30C (100 mg) and azetidine hydrochloride (20 mg) in acetonitrile(2 mL) at 25° C. was treated with DIEA (44 μL) and sodiumtriacetoxyborohydride (67 mg), stirred for 16.5 hours, absorbed ontosilica gel, concentrated, and flash chromatographed on silica gel with5% methanol/dichloromethane and 10% methanol/NH₃-saturateddichloromethane.

EXAMPLE 30E

This example was prepared by substituting EXAMPLE 30D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.20 (d, 1H),7.81 (dd, 1H), 7.71 (d, 2H), 7.35 (m, 14H), 6.88 (d, 1H), 6.78 (d, 2H),4.05 (m, 1H), 3.79 (m, 4H), 3.33 (m, 5H), 3.13 (m, 5H), 2.40 (m, 4H),2.24 (m, 2H), 1.89 (m, 2H).

EXAMPLE 31A

A mixture of 3,6-dioxa-bicyclo[3.1.0]hexane (3.44 g) and sodium azide(5.2 g) in water (10 mL) at 60° C. was stirred for 24 hours andextracted with ethyl acetate. The extract was dried (MgSO₄), filtered,and concentrated. The concentrate was flash chromatographed on silicagel with 0-40% ethyl acetate/hexanes.

EXAMPLE 31B

A mixture of EXAMPLE 31A (3.23 g), di-tert-butyl-dicarbonate (8.73 g),and 20 wt % palladium hydroxide on carbon (200 mg) in ethanol (15 mL) at25° C. was treated with triethylsilane (4.651 g), stirred at 50° C. for16 hours, filtered, and concentrated. The concentrate recrystallizedfrom ethyl acetate/hexanes.

EXAMPLE 31C

A mixture of EXAMPLE 31B (2.03 g) and diphenyldisulfide (2.401 g) intoluene (20 mL) at 25° C. was treated with tributylphosphine (2.224 g),stirred for 16 hours at 80° C., and concentrated. The concentrate wasflash chromatographed on silica gel with 0%-40% ethyl acetate/hexanes.

EXAMPLE 31D

EXAMPLE 31C (590 mg) in 1:1 dioxane/dichloromethane (8 mL) at 25° C. wastreated with 4M HCl in dioxane (5 mL), stirred for 16 hours, andconcentrated. The concentrate triturated with diethyl ether andfiltered.

EXAMPLE 31E

This example was prepared by substituting EXAMPLE 31D for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 31F

This example was prepared by substituting EXAMPLE 31E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (s, 1H), 9.70 (s, 1H),8.69 (d, 1H), 8.54 (d, 1H), 7.87 (dd, 1H), 7.78 (d, 2H), 7.74 (br s,1H), 7.52 (d, 4H), 7.39 (d, 2H), 7.34 (bd, 1H), 7.27 (m, 3H), 7.08 (t,2H), 6.98 (t, 1H), 6.93 (d, 2H), 4.74 (quintet, 1H), 4.45 (q, 1H), 4.33(dd, 1H), 4.17 (dd, 1H), 3.86 (br s, 2H), 3.77 (t, 1H), 3.75 (t, 1H),3.49 (br s, 4H), 3.12 (br s, 2H), 2.89 (s, 2H).

EXAMPLE 32A

A mixture of magnesium turnings (432 mg) and one iodine crystal indiethyl ether (30 mL) at 25° C. was treated with 2-bromobenzyl bromide(4.5 g), stirred for 3 hours, cooled to 0° C., treated with4-(4-oxo-piperidine-1-yl)benzoic acid ethyl ester, prepared as describedin Synthesis 1981, 606-608, (3.7 g) in 1:1 diethyl ether/THF (40 mL),stirred at 25° C. for 18 hours, treated with aqueous NH₄Cl and extractedwith ethyl acetate. The extract was dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 50% ethyl acetate/hexanes.

EXAMPLE 32B

EXAMPLE 32A (1.6 g) in THF (20 mL) at 25° C. was treated with 60% oilysodium hydride (288 mg), heated at 50° C. for 2 hours, treated with HMPA(3 mL) and methyl iodide (3.0 mL), stirred at reflux for 18 hours,cooled to 0° C., treated with aqueous NaHSO₄, and extracted with ethylacetate. The extract was dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 10%-15% ethylacetate/hexanes.

EXAMPLE 32C (and 25% (w/w) EXAMPLE 32B)

A mixture of EXAMPLE 32B (640 mg), 4-chlorophenyl-boronic acid (465 mg),Pd(dppf)Cl₂ (122 mg), and cesium carbonate (1.46 g) in DMF (15 mL) at80° C. was stirred for 2 days and treated with ethyl acetate and brine.The water layer was extracted with ethyl acetate, and the extract wasdried (Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 5%-15% ethyl acetate/hexanes.

EXAMPLE 32D

This example was obtained by substituting EXAMPLE 32C for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 32E

This example was prepared by substituting EXAMPLE 32D for EXAMPLE 2C inEXAMPLE 2D and purified by high pressure liquid chromatography on aWaters Symmetry C₈ column (25 mm×100 mm, 7 μm particle size) with10-100% acetonitrile/0.1% aqueous TFA over 8 minutes at a flow rate of40 mL/minute. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.54 (d, 1H),8.28 (d, 1H), 7.86 (dd, 1H), 7.69 (d, 2H), 7.46 (d, 2H), 7.28 (m, 7H),7.15 (m, 4H), 6.82 (d, 2H), 4.18 (m, 1H), 3.40 (m, 4H), 3.13 (m, 2H),3.04 (s, 3H), 2.86 (m, 4H), 2.74 (s, 6H), 2.14 (m, 2H), 1.47 (d, 2H),1.18 (t, 2H).

EXAMPLE 33

This example was prepared by substituting4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, and EXAMPLE 32D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene-sulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D and purified by highpressure liquid chromatography on a Waters Symmetry C₈ column (25 mm×100mm, 7 μm particle size) with 10-100% acetonitrile/0.1% aqueous TFA over8 minutes at a flow rate of 40 mL/minute. ¹H NMR (400 MHz, DMSO-d₆) δ9.71 (s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.69 (d, 2H),7.46 (d, 2H), 7.30 (m, 7H), 7.14 (m, 4H), 6.82 (d, 2H), 4.18 (m, 1H),3.95 (m, 2H), 3.67 (m, 4H), 3.39 (m, 4H), 3.19 (m, 2H), 3.03 (s, 3H),3.00 (m, 2H), 2.85 (m, 4H), 2.17 (m, 2H), 1.47 (d, 2H), 1.17 (t, 2H).

EXAMPLE 34

EXAMPLE 27E (6.7 g) in DME (50 mL) at −15° C. was treated with NMM (920μL) and isobutyl chloroformate (1.09 mL), stirred for 20 minutes,treated with sodium borohydride (1.59 g) in water (10 mL), stirred for30 minutes, treated with water, and extracted with ethyl acetate. Theextract was washed with water and brine and dried (Na₂SO₄), filtered,and concentrated. The concentrate was flash chromatographed on silicagel with dichloromethane, 1:1 dichloromethane/ethyl acetate, and 10%methanol/dichloromethane. ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (d, 1H), 8.49(d, 1H), 7.83 (dd, 1H), 7.74 (d, 2H), 7.47 (m, 4H), 7.53-7.36 (m, 3H),7.25 (m 2H), 7.19-7.07 (m, 4H), 6.91 (d, 2H), 4.69 (m, 1H), 4.21 (m,1H), 3.49 (m, 2H), 3.35 (t, 2H), 3.31 (m, 8H), 3.27 (m, 2H), 1.89 (m,2H).

EXAMPLE 35A

EXAMPLE 34 (786 mg) in dichloromethane (5 mL) at 25° C. was treated withpara-toluenesulfonic anhydride (326 mg), N,N-dimethylaminopyridine (122mg), and DIEA (350 μL), stirred for 18 hours, treated with ethylacetate, washed with 1% HCl, saturated NaHCO₃, and brine, and dried(Na₂SO₄), filtered, and concentrated.

EXAMPLE 35B

EXAMPLE 35A (100 mg) in DMF (2 mL) at 25° C. was treated with DIEA (100μL) and isopropylamine (60 μL), stirred at 50° C. for 18 hours, treatedwith ethyl acetate, washed with saturated NaHCO₃, water, and brine, anddried (Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with dichloromethane, 1:1dichloromethane/ethyl acetate, and 10% (7M NH₃ in methanol) indichloromethane. ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.09 (d, 1H),7.84 (dd, 1H), 7.72 (d, 2H), 7.47 (m, 4H), 7.40-7.31 (m, 4H), 7.25 (m3H), 7.17 (m, 2H), 6.94 (d, 1H), 6.78 (d, 2H), 4.11 (m, 1H), 3.37 (m,2H), 3.30 (m, 8H), 3.12 (m, 2H), 2.99 (m, 2H), 2.40 (m, 2H), 2.05 (m,2H), 1.16 (m, 6H).

EXAMPLE 36A

This example was made by substituting 2-napthaleneboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 36B

This example was made by substituting EXAMPLE 36A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 36C

This example was made by substituting EXAMPLE 36B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (br s, 1H), 9.98 (br s,1H), 9.60 (br s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.81(d, 2H), 7.49 (tt, 2H), 7.41 (m, 3H), 7.35 (m, 3H), 7.23 (m, 3H), 7.18(d, 2H), 7.12 (m, 2H), 7.02 (d, 2H), 4.19 (m, 1H), 3.99 (br s, 2H), 3.39(d, 4H), 3.29 (m, 4H), 3.14 (m, 2H), 2.98 (m, 2H), 2.75 (s, 6H), 2.14(dd, 2H).

EXAMPLE 37A

This example was made by substituting 1-napthaleneboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 37B

This example was made by substituting. EXAMPLE 37A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 37C

This example was made by substituting EXAMPLE 37B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 9.59 (br s,2H), 8.54 (d, 1H), 8.29 (d, 1H), 8.01 (dd, 2H), 7.85 (dd, 2H), 7.74 (d,2H), 7.59 (m; 4H), 7.47 (m, 2H), 7.35 (d, 1H), 7.24 (m, 3H), 7.18 (d,2H), 7.12 (m, 2H), 6.88 (d, 2H), 4.19 (m, 1H), 3.75 (br s, 2H), 3.39 (d,4H), 3.29 (m, 4H), 3.14 (m, 2H), 2.98 (m, 2H), 2.75 (s, 6H), 2.15 (dd,2H).

EXAMPLE 38A

This example was made by substituting 3-cyanophenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 38B

This example was made by substituting EXAMPLE 38A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 38C

This example was made by substituting EXAMPLE 38B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 9.47 (br s,2H), 8.54 (d, 1H), 8.29 (d, 1H), 7.89 (d, 1H), 7.86 (dd, 2H), 7.77 (d,2H), 7.69 (m, 3H), 7.56 (m, 2H), 7.37 (m, 1H), 7.24 (m, 2H), 7.14 (d,5H), 6.93 (d, 2H), 4.18 (m, 1H), 4.04 (m, 2H), 3.75 (m, 2H), 3.39 (d,4H), 3.15 (m, 4H), 3.06 (m, 2H), 2.75 (s, 3H), 2.74 (s, 3H), 2.14 (dd,2H).

EXAMPLE 39A

This example was made by substituting 3-methoxyphenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 39B

This example was made by substituting EXAMPLE 39A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 39C

This example was made by substituting EXAMPLE 39B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 9.58 (br s,1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.72 (m,1H), 7.50 (m, 2H), 7.37 (m, 2H), 7.24 (m, 2H), 7.14 (d, 4H), 6.98 (m,1H), 6.92 (m, 4H), 4.31 (br s, 2H), 4.18 (m, 1H), 3.79 (s, 3H), 3.39 (d,3H), 3.15 (m, 5H), 2.75 (s, 6H), 2.14 (dd, 2H).

EXAMPLE 40A

This example was made by substituting 3-chlorophenyl-boronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 40B

This example was made by substituting EXAMPLE 40A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 40C

This example was made by substituting EXAMPLE 40B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 9.86 (br s,1H), 9.59 (br s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77(d, 2H), 7.70 (m, 1H), 7.49 (m, 5H), 7.34 (m, 2H), 7.24 (m, 2H), 7.14(d, 4H), 6.94 (d, 2H), 4.19 (m, 1H), 3.39 (d, 3H), 3.13 (m, 5H), 2.88(m, 2H), 2.75 (s, 6H), 2.15 (dd, 2H).

EXAMPLE 41A

This example was made by substituting 2-chlorophenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 41B

This example was made by substituting EXAMPLE 41A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 41C

This example was made by substituting EXAMPLE 41B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (br s, 1H), 10.00 (br s,1H), 9.59 (br s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77(d, 2H), 7.76 (m, 1H), 7.58 (m, 3H), 7.45 (m, 3H), 7.28 (dd, 1H), 7.23(m, 2H), 7.14 (d, 4H), 6.94 (d, 2H), 4.18 (m, 1H), 3.39 (d, 3H), 3.13(m, 5H), 3.02 (m, 2H), 2.75 (s, 6H), 2.15 (dd, 2H).

EXAMPLE 42A

This example was made by substituting 3,4-methylene-dioxybenzeboronicacid for 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 42B

This example was made by substituting EXAMPLE 42A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 42C

This example was made by substituting EXAMPLE 42B for

EXAMPLE 2C in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br s, 1H),9.85 (br s, 1H), 9.55 (br s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.86 (dd,1H), 7.77 (d, 2H), 7.69 (m, 1H), 7.48 (br s, 2H), 7.31 (m, 1H), 7.23 (m,2H), 7.14 (d, 4H), 6.96 (m, 4H), 6.79 (dd, 1H), 6.06 (s, 2H), 4.18 (m,1H), 3.39 (d, 3H), 3.12 (m, 5H), 2.86 (m, 2H), 2.75 (s, 6H), 2.14 (dd,2H).

EXAMPLE 43A

This example was made by substituting thiophene-3-boronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 43B

This example was made by substituting EXAMPLE 43A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 43C

This example was made by substituting EXAMPLE 43B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (br s, 1H), 9.99 (br s,1H), 9.62 (br s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.78(d, 2H), 7.69 (m, 2H), 7.63 (s, 1H), 7.48 (br s, 2H), 7.41 (m, 1H), 7.24(m, 2H), 7.14 (d, 5H), 6.95 (d, 2H), 4.18 (m, 1H), 3.39 (d, 3H), 3.14(m, 5H), 2.89 (m, 2H), 2.75 (s, 6H), 2.15 (dd, 2H).

EXAMPLE 44A

This example was made by substituting pyridine-3-boronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 44B

This example was made by substituting EXAMPLE 44A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 44C

This example was made by substituting EXAMPLE 44B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br s, 1H), 9.99 (br s,1H), 9.66 (br s, 1H), 8.69 (dd, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.95(d, 1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.59 (m, 3H), 7.40 (m, 1H), 7.24(m, 2H), 7.14 (d, 4H), 6.93 (d, 2H), 4.19 (m, 1H), 3.39 (d, 3H), 3.14(m, 5H), 2.92 (m, 2H), 2.75 (s, 6H), 2.15 (dd, 2H).

EXAMPLE 45A

This example was made by substituting 8-quinolineboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 45B

This example was made by substituting EXAMPLE 45A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 45C

This example was made by substituting EXAMPLE 45B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 9.84 (br s,1H), 9.61 (br s, 1H), 8.84 (dd, 1H), 8.54 (d, 1H), 8.48 (dd, 1H), 8.29(d, 1H), 8.10 (td, 1H), 7.85 (dd, 1H), 7.80 (d, 1H), 7.73 (m, 4H), 7.56(m, 3H), 7.35 (dd, 1H), 7.23 (m, 3H), 7.14 (m, 3H), 6.89 (d, 2H), 4.29(m, 1H), 4.20 (m, 1H), 3.90 (d, 1H), 3.39 (d, 4H), 3.14 (m, 3H), 2.97(m, 3H), 2.75 (s, 6H), 2.15 (dd, 2H).

EXAMPLE 46A

This example was made by substituting benzofuran-2-boronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 46B

This example was made by substituting EXAMPLE 46A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 46C

This example was made by substituting EXAMPLE 46B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (br s, 1H), 9.81 (br s,1H), 9.63 (br s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.97 (d, 1H), 7.86(dd, 1H), 7.81 (d, 2H), 7.69 (m, 3H), 7.60 (m, 2H), 7.46 (s, 1H), 7.38(td, 1H), 7.32 (t, 1H), 7.22 (m, 2H), 7.15 (d, 4H), 7.01 (d, 2H), 4.19(m, 1H), 3.39 (d, 3H), 3.27 (m, 2H), 3.15 (m, 5H), 2.75 (s, 6H), 2.15(dd, 2H).

EXAMPLE 44A

This example was made by substituting 2-methylphenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 44B

This example was made by substituting EXAMPLE 44A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 44C

This example was made by substituting EXAMPLE 44B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br s, 1H), 9.94 (br s,1H), 9.73 (br s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77(d, 2H), 7.74 (m, 1H), 7.50 (m, 2H), 7.31 (d, 2H), 7.22 (m, 9H), 6.94(d, 2H), 4.19 (m, 1H), 3.39 (d, 4H), 3.16 (m, 4H), 2:92 (m, 2H), 2.75(s, 6H), 2.15 (dd, 2H).

EXAMPLE 48A

This example was made by substituting 3-quinolineboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 48B

This example was made by substituting EXAMPLE 48A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 48C

This example was made by substituting EXAMPLE 48B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 9.93 (br s,1H), 9.56 (br s, 1H), 8.53 (d, 1H), 8.42 (s, 1H), 8.28 (d, 1H), 8.09 (d,1H), 8.04 (dd, 1H), 7.85 (dd, 1H), 7.82 (m, 2H), 7.74 (d, 2H), 7.68 (td,1H), 7.50 (m, 2H), 7.23 (m, 2H), 7.14 (d, 4H), 6.90 (d, 2H), 4.19 (m,1H), 3.39 (d, 3H), 3.14 (m, 5H), 2.90 (m, 2H), 2.74 (s, 6H), 2.13 (dd,2H).

EXAMPLE 49A

A mixture of EXAMPLE 1A (272 mg), 1-bromo-naphthalene-2-carbaldehyde(0.409 g), MP-BH₃CN (2.47 mmol/g, 1.41 g) and acetic acid (0.14 g) in1:1 methanol/dichloromethane (8 mL) was shaken for 1 day at 25° C.,filtered, and concentrated. The concentrate was treated with saturatedaqueous K₂CO₃ and dichloromethane, and the organic layer was dried(MgSO₄), filtered and concentrated. The concentrate was flashchromatographed on silica gel with 5%-50% ethyl acetate/hexanes.

EXAMPLE 49B

This example was made by substituting EXAMPLE 49A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 49C

This example was made by substituting EXAMPLE 49B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 49D

This example was made by substituting EXAMPLE 49C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene-sulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)-methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (br s,1H), 9.87 (br s, 1H), 8.76 (t, 1H), 8.60 (d, 1H), 8.29 (d, 1H), 8.13 (d,1H), 8.04 (d, 1H), 7.90 (dd, 1H), 7.86 (d, 1H), 7.77 (d, 2H), 7.62 (d,2H), 7.60 (m, 1H), 7.50 (t, 1H), 7.37 (m, 3H), 7.28 (d, 2H), 7.19 (m,2H), 6.94 (d, 2H), 4.23 (br s, 2H), 3.82 (br s, 4H), 3.67 (dd, 2H), 3.28(m, 2H), 3.16 (br s, 2H), 2.97 (br s, 2H).

EXAMPLE 50

This example was made by substituting EXAMPLE 49C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) 67 12.12 (br s, 1H), 9.97 (br s,1H), 9.56 (br s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 8.12 (d, 1H), 8.05 (d,1H), 7.87 (d, 1H), 7.86 (d, 1H), 7.79 (d, 2H), 7.61 (m, 3H), 7.50 (m,1H), 7.38 (d, 2H), 7.28 (d, 1H), 7.22 (m, 2H), 7.14 (m, 4H), 6.95 (d,2H), 4.25 (br s, 2H), 4.19 (m, 1H), 3.39 (d, 3H), 3.14 (m, 5H), 2.94 (m,2H), 2.75 (s, 3H), 2.74 (s, 3H), 2.15 (dd, 2H).

EXAMPLE 51

This example was made by substituting EXAMPLE 49C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. NMR (400 MHz, DMSO-d₆) δ 12.11 (br s, 1H),9.89 (br s, 2H), 8.55 (d, 1H), 8.29 (d, 1H), 8.12 (d, 1H), 8.04 (d, 1H),7.86 (m, 2H), 7.78 (d, 2H), 7.62 (d, 2H), 7.60 (m, 1H), 7.50 (t, 1H),7.38 (d, 2H), 7.28 (d, 1H), 7.15 (d, 4H), 6.95 (d, 2H), 4.19 (m, 1H),3.95 (m, 4H), 3.62 (m 3H), 3.41 (d, 5H), 3.18 (m, 5H), 3.01 (br s, 4H),2.19 (dd, 2H).

EXAMPLE 52A

A mixture of 6-oxa-bicyclo[3.1.0]hexane (1.68 g) and NaN₃ (2.6 g) inwater (5 mL) at 60° C. was stirred for 3 days. The water layer wasextracted with dichloromethane, and the extract was dried (MgSO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel 0-40% ethyl acetate/hexanes.

EXAMPLE 52B

A mixture of EXAMPLE 52A (1.017 g), di(tert-butyl) dicarbonate (2.619g), Pd(OH)₂ (100 mg) and triethylsilane (1.395 g) in ethanol (15 mL) at50° C. was stirred for 16 hours, concentrated partially, and partitionedbetween ethyl acetate and water. The extract was dried (MgSO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel with 10-60% ethyl acetate/hexanes.

EXAMPLE 52C

A mixture of EXAMPLE 52B (0.201 g) and diphenyldisulfide (262 mg) intoluene (2 mL) at 25° C. was treated with tri-n-butylphosphine (243 mg),stirred for 16 hours at 80° C., and concentrated. The concentrate wasflash chromatographed on silica gel 0-30% ethyl acetate/hexanes.

EXAMPLE 52D

A mixture of EXAMPLE 52C (0.325 g) and 4M HCl in dioxane (2.5 mL) indichloromethane (3 mL) at 25° C. was stirred for 3 hours and partiallyconcentrated. The concentrate was treated with diethyl ether andfiltered.

EXAMPLE 52E

This example was prepared by substituting EXAMPLE 52D for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 52F

This example was made by substituting EXAMPLE 52E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamide,in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br s, 1H), 9.77 (br s,1H), 8.55 (d, 1H), 8.36 (d, 1H), 7.85 (dd, 1H), 7.77 (d, 2H), 7.73 (m,1H), 7.54 (m, 4H), 7.39 (td, 2H), 7.33 (m, 3H), 7.17 (m, 4H), 6.93 (d,2H), 4.32 (br s, 2H), 4.10 (br s, 2H), 4.09 (quintet, 1H), 3.85 (q, 1H),3.39 (d, 3H), 3.25 (br s, 2H), 3.10 (br s, 2H), 2.89 (br s, 2H), 2.25(sextet, 2H), 1.79 (m, 2H), 1.64 (m, 2H).

EXAMPLE 53

This example was made by substituting EXAMPLE 52E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,in EXAMPLE 32E. ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (br s, 1H), 8.55 (d,1H), 8.35 (d, 1H), 7.85 (dd, 1H), 7.68 (d, 2H), 7.42 (t, 2H), 7.35 (m,3H), 7.28 (m, 3H), 7.16 (m, 4H), 6.82 (d, 2H), 4.09 (quintet, 1H), 3.84(q, 1H), 3.39 (d, 2H), 3.03 (s, 3H), 2.89 (s, 2H), 2.83 (t, 1H), 2.25(sextet, 2H), 1.79 (m, 2H), 1.64 (m, 2H), 1.47 (d, 2H), 1.17 (m, 2H).

EXAMPLE 54

This example was made by substituting3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 4C. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (br s, 1H), 9.72 (br s,1H), 8.76 (t, 1H), 8.60 (d, 1H), 7.90 (dd, 1H), 7.75 (d, 2H), 7.71 (m,1H), 7.52 (br s, 2H), 7.41 (dd, 2H), 7.35 (m, 2H), 7.28 (m, 2H), 7.19(m, 2H), 6.92 (d, 2H), 4.24 (br s, 2H), 3.80 (br s, 2H), 3.66 (q, 2H),3.28 (t, 2H), 3.14 (br s, 2H), 2.86 (br s, 2H).

EXAMPLE 55A

This example was made by substituting 3,4-dichlorophenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 55B

This example was made by substituting EXAMPLE 55A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 55C

This example was made by substituting EXAMPLE 55B and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (br s,1H), 9.71 (br s, 1H), 8.76 (t, 1H), 8.60 (d, 1H), 7.90 (dd, 1H), 7.76(d, 2H), 7.73 (m, 1H), 7.71 (d, 2H), 7.54 (m, 2H), 7.36 (m, 4H), 7.26(tt, 2H), 7.18 (m, 2H), 6.94 (d, 2H), 4.28 (br s, 2H), 3.85 (br s, 2H),3.67 (q, 2H), 3.28 (t, 2H), 3.12 (br s, 2H), 2.93 (br s, 2H).

EXAMPLE 56

This example was made by substituting EXAMPLE 55B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 9.94 (br s,1H), 9.64 (br s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.78(d, 2H), 7.74 (m, 1H), 7.71 (d, 1H), 7.69 (br s, 1H), 7.54 (m, 2H), 7.37(m, 2H), 7.23 (m, 2H), 7.14 (m, 4H), 6.95 (d, 2H), 4.31 (br s, 2H), 4.20(m, 1H), 3.93 (br s, 2H), 3.39 (d, 3H), 3.14 (m, 5H), 2.90 (m, 2H), 2.75(s, 6H), 2.15 (dd, 2H).

EXAMPLE 57

This example was made by substituting EXAMPLE 55B and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (br s,1H), 10.32 (br s, 1H), 9.98 (br s, 1H), 8.55 (d, 1H), 8.30 (d, 1H), 7.87(dd, 1H), 7.77 (d, 2H), 7.71 (br s, 1H), 7.70 (d, 2H), 7.53 (m, 2H),7.36 (m, 2H), 7.24 (m, 2H), 7.15 (m, 4H), 6.94 (d, 2H), 4.25 (br s, 2H),4.19 (m, 1H), 3.95 (m, 4H), 3.63 (m, 3H), 3.40 (d, 5H), 3.19 (m, 4H),3.02 (br s, 4H), 2.18 (dd, 2H).

EXAMPLE 58A

This example was made by substituting 4-trifluoromethylphenylboronicacid for 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 58B

This example was made by substituting EXAMPLE 58A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 58C

This example was made by substituting EXAMPLE 58B and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (br s,1H), 9.85 (br s, 1H), 8.76 (t, 1H), 8.60 (d, 1H), 7.90 (dd, 1H), 7.83(d, 2H), 7.78 (br s, 1H), 7.76 (d, 2H), 7.61 (d, 2H), 7.54 (m, 2H), 7.37(m, 3H), 7.26 (t, 2H), 7.19 (t, 2H), 6.93 (d, 2H), 4.30 (br s, 2H), 4.00(br s, 4H), 3.67 (q, 2H), 3.28 (t, 2H), 3.10 (br s, 2H), 2.94 (br s,2H).

EXAMPLE 59

This example was made by substituting EXAMPLE 58B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br s, 1H), 10.01 (br s,1H), 9.60 (br s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.82(d, 2H), 7.78 (br s, 1H), 7.77 (d, 2H), 7.61 (d, 2H), 7.56 (m, 2H), 7.37(m, 1H), 7.23 (m, 2H), 7.14 (m, 4H), 6.93 (d, 2H), 4.25 (br s, 2H), 4.19(m, 1H), 3.98 (br s, 2H), 3.39 (d, 3H), 3.13 (m, 5H), 2.90 (m, 2H), 2.74(s, 6H), 2.15 (dd, 2H).

EXAMPLE 60

This example was made by substituting EXAMPLE 58B and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br s,1H), 9.99 (br s, 2H), 8.55 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.83(d, 2H), 7.79 (br s, 1H), 7.77 (d, 2H), 7.60 (d, 2H), 7.57 (m, 2H), 7.38(m, 1H), 7.23 (m, 2H), 7.14 (m, 4H), 6.93 (d, 2H), 4.32 (br s, 2H), 4.19(m, 1H), 3.95 (m, 2H), 3.62 (m, 3H), 3.40 (m, 5H), 3.20 (m, 4H), 3.02(br s, 4H), 2.18 (dd, 2H).

EXAMPLE 61A

This example was made by substituting 4-trifluoromethoxyboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 61B

This example was made by substituting EXAMPLE 61A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 61C

This example was made by substituting EXAMPLE 61B and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (br s,1H), 9.78 (br s, 1H), 8.76 (t, 1H), 8.60 (d, 1H), 7.90 (dd, 1H), 7.76(d, 2H), 7.75 (br s, 1H), 7.54 (m, 2H), 7.50 (d, 2H), 7.45 (d, 2H), 7.37(m, 3H), 7.26 (t, 2H), 7.18 (m, 2H), 6.93 (d, 2H), 4.30 (br s, 2H), 3.98(br s, 4H), 3.67 (q, 2H), 3,28 (t, 2H), 3.11 (br s, 2H), 2.89 (br s,2H).

EXAMPLE 62

This example was made by substituting EXAMPLE 61B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 10.05 (br s,1H), 9.62 (br s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77(d, 2H), 7.76 (br s, 1H), 7.54 (m, 2H), 7.50 (d, 2H), 7.45 (d, 2H), 7.37(m, 1H), 7.23 (m, 2H), 7.14 (m, 4H), 6.93 (d, 2H), 4.31 (br s, 2H), 4.19(m, 1H), 3.82 (br s, 2H), 3.39 (d, 3H), 3.13 (m, 5H), 2.92 (m, 2H), 2.74(s, 6H), 2.15 (dd, 2H).

EXAMPLE 63

This example was made by substituting EXAMPLE 61B and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (br s,1H), 9.99 (br s, 2H), 8.55 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.77(d, 2H), 7.76 (br s, 1H), 7.54 (m, 2H), 7.51 (d, 2H), 7.45 (d, 2H), 7.37(m, 1H), 7.23 (m, 2H), 7.14 (m, 4H), 6.93 (d, 2H), 4.30 (br s, 2H), 4.20(m, 1H), 3.95 (m, 2H), 3.63 (m, 3H), 3.40 (m, 5H), 3.20 (m, 4H), 3.02(br s, 4H), 2.18 (dd, 2H).

EXAMPLE 64A

This example was made by substituting 4-phenoxyphenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 64B

This example was made by substituting EXAMPLE 64A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 64C

This example was made by substituting EXAMPLE 64B and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (br s,1H), 9.76 (br s, 1H), 8.76 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.77(d, 2H), 7.73 (br s, 1H), 7.52 (m, 2H), 7.38 (m, 7H), 7.26 (t, 2H), 7.18(m, 3H), 7.07 (m, 4H), 6.94 (d, 2H), 4.36 (br s, 2H), 3.80 (br s, 4H),3.67 (q, 2H), 3.28 (t, 2H), 3.15 (br s, 2H), 2.87 (br s, 2H).

EXAMPLE 65

This example was made by substituting EXAMPLE 64B and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (br s,1H), 9.98 (br s, 2H), 8.56 (d, 1H), 8.30 (d, 1H), 7.87 (dd, 1H), 7.78(d, 2H), 7.73 (br s, 1H), 7.51 (m, 2H), 7.38 (m, 5H), 7.23 (m, 2H), 7.15(m, 5H), 7.07 (d, 4H), 6.95 (d, 2H), 4.31 (br s, 2H), 4.20 (m, 1H), 3.94(m, 2H), 3.63 (m, 3H), 3.40 (m, 5H), 3.19 (m, 4H), 3.02 (br s, 4H), 2.18(dd, 2H).

EXAMPLE 66A

ADDP (11.43 g) in THF (100 mL) at 25° C. was treated withtributylphosphine (9.16 g), stirred for 10 minutes, treated with(S)-3-tert-butoxycarbonylamino-4-hydroxybutyric acid cyclohexyl ester(9.1 g), prepared as described in Tet. Lett. (1995), 36(8), 1223, in THF(20 mL) and thiophenol (6.61 g), stirred for 2 days, treated withdiethyl ether, and filtered. The filtrate was concentrated, and theconcentrate was flash chromatographed on silica gel with 0-15% ethylacetate/hexane.

EXAMPLE 66B

A mixture of EXAMPLE 66A (7.1 g) and 4M HCl in dioxane (30 mL) wasstirred for 5 hours and concentrated.

EXAMPLE 66C

This example was made by substituting EXAMPLE 66B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 66D

A mixture of EXAMPLE 66C (8.341 g) and lithium hydroxide (1.426 g) in1:1 THF/water (100 mL) was stirred for 18 hours at 25° C., partiallyconcentrated, treated with water (250 mL), washed withdichloromethane/ethyl acetate, acidified with 12M HCl to pH 2, andextracted with ethyl acetate. The extract was washed with water andbrine and dried (MgSO₄), filtered, and concentrated.

EXAMPLE 66E

A mixture of EXAMPLE 66D (6.42 g) and NMM (1.67 g) in DME (70 mL) at0-5° C. was treated with isobutyl chloroformate (2.14 mL), stirred for 5minutes treated with 2M dimethylamine in THF (40 mL), stirred at 25° C.,concentrated, and filtered.

EXAMPLE 66F

This example was made by substituting EXAMPLE 66E for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 66G

This example was made by substituting EXAMPLE 66F for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 9.69 (br s, 1H), 8.47 (d,1H), 8.19 (d, 1H), 7.82 (dd, 1H), 7.72 (d, 2H), 7.51 (m, 1H), 7.47 (s,4H), 7.37 (m, 2H), 7.30 (m, 2H), 7.24 (t, 3H), 7.16 (m, 1H), 6.93 (d,1H), 6.80 (d, 2H), 4.07 (br s, 2H), 3.39 (m, 2H), 3.33 (m, 2H), 3.14 (m,4H), 3.00 (m, 2H), 2.63 (s, 6H),2.40 (m, 4H), 2.08 (m, 2H).

EXAMPLE 67A

ADDP (16.94 g) in THF (90 mL) at 25° C. was treated withtributylphosphine (13.55 g), stirred for 10 minutes, treated with(2-hydroxy-1,1-dimethylethyl)carbamic acid tert-butyl ester (8.47 g),prepared as described in Synlett. (1997), (8), 893-894, in THF (30 mL)and thiophenol (7.38 g), stirred for 1 day, treated with diethyl ether,and filtered. The filtrate was concentrated, and the concentrate wasflash chromatographed on silica gel 0-15% ethyl acetate/hexanes.

EXAMPLE 67B

A mixture of EXAMPLE 67A (0.562 g) and 80% magnesium monoperoxy pthalicacid (1.36 g) in THF (10 mL) was stirred for 18 hours, treated withdichloromethane, and filtered. The filtrate was washed with brine anddried (MgSO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel 10-50% ethyl acetate/hexanes.

EXAMPLE 67C

This example was made by substituting EXAMPLE 67B for EXAMPLE 66A inEXAMPLE 66B.

EXAMPLE 67D

This example was made by substituting EXAMPLE 67C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 67 E

This example was made by substituting EXAMPLE 67D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (br s, 1H), 9.69 (br s,1H), 8.44 (d, 1H),8.33 (s, 1H), 7.82 (d, 2H), 7.71 (dd, 2H), 7.64 (td,2H), 7.52 (d, 3H), 7.40 (d, 2H), 7.32 (m, 1H), 7.25 (d, 1H), 7.23 (tt,1H), 7.16 (tt, 2H), 6.95 (d, 2H), 4.30 (br s, 2H), 4.13 (s, 2H), 3.84(br s, 2H), 3.13 (br s, 4H), 2.86 (br s, 2H), 1.62 (s, 6H).

EXAMPLE 68A

This example was made by substituting 2,4-dichlorophenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 68B

This example was made by substituting EXAMPLE 68A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 68C

This example was made by substituting EXAMPLE 68B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 9.89 (br s,1H), 9.56 (br s, 1H), 8.54 (d, 1H), 8.28 (d, 1H), 7.85 (dd, 1H), 7.77(d, 2H), 7.74 (m, 1H), 7.52 (m, 3H), 7.43 (d, 1H), 7.26 (d, 1H), 7.22(d, 2H), 7.13 (m, 4H), 6.94 (d, 2H), 4.26 (br s, 2H), 4.17 (m, 1H), 3.38(d, 3H), 3.13 (m, 7H), 2.74 (s, 6H), 2.14 (dd, 2H).

EXAMPLE 69A

This example was made by substituting thiophene-2-boronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 69B

This example was made by substituting EXAMPLE 69A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 69C

This example was made by substituting EXAMPLE 69B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (br s, 1H), 9.95 (br s,1H), 9.55 (br s, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.85 (dd, 1H), 7.78(d, 2H), 7.73 (m, 1H), 7.68 (d, 1H), 7.51 (m, 3H), 7.24 (m, 2H), 7.17(m, 2H), 7.14 (m, 4H), 6.96 (d, 2H), 4.41 (br s, 2H), 4.18 (m, 1H), 3.38(d, 3H), 3.13 (m, 7H), 2.75 (s, 6H), 2.15 (dd, 2H).

EXAMPLE 70A

This example was made by substituting 4-chloro-2-methylphenylboronicacid for 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 70B

This example was made by substituting EXAMPLE 70A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 70C

This example was made by substituting EXAMPLE 70B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (m, 1H), 9.60 (s, 1H),8.53 (d, 1H), 8.28 (d, 1H), 7.85 (dd, 1H), 7.77 (d, 3H), 7.52 (m, 2H),7.41 (d, 1H), 7.31 (dd, 1H), 7.20 (m, 4H), 7.12 (m, 4H), 6.94 (d, 1H),4.18 (m, 1H), 3.85 (m, 7H), 3.38 (d, 2H), 3.11 (m, 6H), 2.74 (s, 6H),2.14 (dd, 2H), 1.96 (s, 3H).

EXAMPLE 71A

This example was made by substituting 2,4-difluorophenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 71B

This example was made by substituting EXAMPLE 71A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 71C

This example was made by substituting EXAMPLE 71B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 9.53 (br s,1H), 8.53 (d, 1H), 8.27 (d, 1H), 7.85 (dd, 1H), 7.76 (d, 2H), 7.54(quintet, 2H), 7.44 (m, 1H), 7.35 (m, 2H), 7.15 (m, 6H), 6.93 (d, 2H),4.17 (m, 1H), 3.38 (d, 2H), 3.12 (m, 4H), 2.74 (s, 3H), 2.73 (s, 3H),2.13 (dd, 2H).

EXAMPLE 72A

This example was made by substituting (2-benzenesulfonylethyl)carbamicacid tert-butyl ester, prepared as described in WO2001-U.S. Pat. No.11,395, for EXAMPLE 66A in EXAMPLE 66B.

EXAMPLE 72B

This example was made by substituting EXAMPLE 72A for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 72C

This example was made by substituting EXAMPLE 72B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 9.60 (br s,1H), 8.56 (d, 1H), 8.55 (m, 1H), 7.91 (dd, 1H), 7.84 (m, 2H), 7.75 (d,3H), 7.67 (tt, 1H), 7.54 (m, 2H), 7.48 (m, 4H), 7.37 (m, 3H), 7.13 (d,2H), 6.92 (d, 2H), 4.40 (br s, 2H), 3.82 (br s, 2H), 3.79 (s, 2H), 3.29(br s, 2H), 3.13 (br s, 2H), 2.81 (br s, 2H).

EXAMPLE 73

This example was made by substituting EXAMPLE 72B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 9.52 (br s,1H), 8.56 (d, 1H), 8.55 (m, 1H), 7.91 (dd, 1H), 7.84 (m, 2H), 7.76 (d,2H), 7.67 (tt, 1H), 7.54 (m, 6H), 7.39 (m, 2H), 7.34 (m, 1H), 7.14 (d,1H), 6.92 (d, 2H), 4.38 (br s, 2H), 3.92 (br s, 2H), 3.78 (s, 4H), 3.26(br s, 2H), 3.09 (br s, 2H), 2.86 (br s, 2H).

EXAMPLE 74

This example was made by substituting EXAMPLE 31E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (br s, 1H), 9.88 (br s,1H), 8.68 (d, 1H), 8.54 (d, 1H), 7.86 (dd, 1H), 7.76 (d, 2H), 7.72 (m,1H), 7.50 (m, 4H), 7.46 (m, 2H), 7.41 (d, 1H), 7.37 (m, 2H), 7.26 (m,2H), 7.07 (t, 2H), 6.97 (t, 1H), 6.92 (d, 2H), 4.73 (quintet, 1H), 4.44(dd, 1H), 4.31 (dd, 1H), 4.24 (br s, 2H), 4.17 (dd, 1H), 3.75 (m, 2H),3.24 (br s, 4H), 2.88 (br s, 4H).

EXAMPLE 75A

This example was made by substituting 5-methylthiophene-2-boronic acidfor 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 75B

This example was made by substituting EXAMPLE 75A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 75C

This example was made by substituting EXAMPLE 75B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 10.00 (br s,1H), 9.58 (br s, 1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.85 (dd, 1H), 7.79(d, 2H), 7.70 (br s, 1H), 7.47 (m, 3H), 7.23 (d, 2H), 7.18 (m, 2H), 7.14(m, 2H), 7.03 (d, 1H), 6.97 (d, 2H), 6.86 (m, 1H), 4.40 (br s, 2H), 4.19(m, 1H), 3.39 (d, 3H), 3.13 (m, 3H), 2.99 (br s, 2H), 2.75 (s, 6H), 2.48(s, 3H), 2.15 (dd, 2H).

EXAMPLE 76A

This example was made by substituting EXAMPLE 31C for EXAMPLE 67A inEXAMPLE 67B.

EXAMPLE 76B

This example was made by substituting EXAMPLE 76A for EXAMPLE 66A inEXAMPLE 66B.

EXAMPLE 76C

This example was made by substituting EXAMPLE 76B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 76D

This example was made by substituting EXAMPLE 76C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 9.87 (br s,1H), 8.50 (d, 1H), 8.48 (d, 1H), 7.82 (d, 2H), 7.77 (dd, 1H), 7.75 (m,1H), 7.71 (dd, 2H), 7.53 (m, 4H), 7.39 (m, 2H), 7.34 (m, 1H), 7.25 (m,3H), 7.12 (d, 1H), 6.96 (d, 2H), 4.88 (sextet, 1H), 4.80 (quintet,1H),4.46 (dd, 1H), 4.28 (br s, 2H), 4.23 (dd, 1H), 4.09 (dd, 1H), 3.86(dd, 1H), 3.14 (br s, 2H), 2.96 (br s, 4H).

EXAMPLE 77

This example was made by substituting EXAMPLE 76c for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (br s, 1H), 9.90 (br s,1H), 8.50 (d, 1H), 8.48 (d, 1H), 7.82 (d, 2H), 7.77 (dd, 1H), 7.75 (m,1H), 7.71 (dd, 2H), 7.52 (m, 2H), 7.48 (t, 2H), 7.42 (t, 1H), 7.36 (m,2H), 7.23 (m, 3H), 7.12 (d, 1H), 6.96 (d, 2H), 4.88 (sextet, 1H), 4.80(quintet, 1H),4.46 (dd, 1H), 4.30 (br s, 2H), 4.22 (dd, 1H), 4.09 (dd,1H), 3.86 (dd, 1H), 3.17 (br s, 2H), 2.89 (br s, 4H).

EXAMPLE 78

This example was made by substituting EXAMPLE 832175D for EXAMPLE 49A inEXAMPLE 49B. ¹H NMR (500 MHz, DMSO-₆) δ 11.96 (br s, 1H), 10.46 (br s,1H), 8.60 (d, 1H), 8.49 (d, 1H), 7.95 (dd, 1H), 7.76 (d, 2H), 7.69 (m,1H), 7.51 (m, 4H), 7.40 (t, 4H), 7.32 (m, 1H), 7.24 (m, 4H), 6.92 (d,2H), 4.69 (br s, 1H), 4.25 (br s, 2H), 3.97 (br s, 2H), 3.68 (m, 2H),3.29 (br s, 4H), 2.91 (s, 3H), 2.75 (br s, 2H).

EXAMPLE 79

This example was made by substituting EXAMPLE 837538C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. NMR (500 MHz, DMSO-d₆) δ ¹H NMR (500 MHz,DMSO-d₆) δ 8.50 (d, 1H), 8.36 (d, 1H), 7.79 (dd, 1H), 7.72 (d, 2H), 7.36(d, 2H), 7.28 (d, 2H), 7.21 (t, 2H), 7.15 (d, 1H), 7.12 (d, 2H), 7.03(d, 1H), 6.84 (d, 2H), 4.13 (m, 1H), 3.52 (m, 4H), 3.38 (m, 4H), 3.21(br s, 4H), 2.82 (br s, 2H), 2.45 (m, 4H), 2.32 (br s, 4H), 2.20 (br s,2H), 2.17 (br s, 2H), 2.00 (m, 1H), 1.86 (m, 1H), 1.67 (m, 4H).

EXAMPLE 81A

This example was made by substituting 4-bromophenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 81B

This example was made by substituting EXAMPLE 81A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 81C

This example was made by substituting EXAMPLE 81B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.06 (br s, 1H), 9.79 (br s,1H), 9.47 (br s, 1H), 8.54 (d, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.77(d, 2H), 7.69 (br s, 1H), 7.64 (d, 2H), 7.50 (m, 2H), 7.35 (m, 3H), 7.23(m, 2H), 7.14 (m, 4H), 6.93 (d, 2H), 4.29 (br s, 2H), 4.19 (m, 1H), 3.77(br s, 2H), 3.14 (m, 3H), 2.74 (s, 6H), 2.14 (dd, 2H).

EXAMPLE 82A

4′-chloro-biphenyl-2-carbonitrile, prepared as described in J. Org.Chem. (1984), 49(9), 1594-1603), (0.35 g) in diethyl ether (25 mL) at−75° C. was treated with titanium isopropoxide (0.53 mL) and 3M ethylmagnesium bromide in diethyl ether (1.2 mL), stirred for 10 minutes,stirred at 25° C. for 1 hour, treated with BF₃-diethyl etherate (0.41mL), stirred for 1 hour, treated with 1M HCl (5 mL) then 10% NaOH (15mL), and extracted with diethyl ether. The extract was dried (MgSO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel 10%-50% ethyl acetate/hexanes).

EXAMPLE 82B

A mixture of 4-(bis(2-methanesulfonyloxyethyl)-amino)benzoic acid ethylester, prepared as described in J. Med. Chem. (1977), 21(1), 16-26,(80.6 mg), EXAMPLE 82A (58.5 mg), and potassium carbonate (69.1 mg) inacetonitrile (5 mL) in a microwave reactor at 160° C. was stirred for 30minutes, treated with ethyl acetate (10 mL), filtered, and concentrated.The concentrate flash chromatographed on silica gel with 10-30% ethylacetate/hexanes.

EXAMPLE 82C

This example was made by substituting EXAMPLE 82B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 82D

This example was made by substituting EXAMPLE 82C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (br s, 1H), 9.49 (br s,1H), 8.54 (d, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.73 (d, 2H), 7.47 (m,5H), 7.38 (m, 2H), 7.23 (d, 2H), 7.14 (m, 5H), 6.89 (d, 2H), 4.18 (m,2H), 3.39 (d, 2H), 3.20 (m, 6H), 2.75 (s, 3H), 2.74 (s, 3H), 2.44 (br s,4H), 2.13 (dd, 2H), 1.01 (br s, 2H), 0.82 (br s, 2H).

EXAMPLE 83A

A mixture of 2M dimethylamine in THF (27 mL),(R)-2-benzyloxycarbonylamino-3-phenylthiopropionic acid (5.8 g), HoBT(2.67 g), and EDAC.HCl (5.2 g) in THF (50 mL) was stirred for 18 hoursat 25° C., treated with water and extracted with dichloromethane. Theextract was dried (MgSO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 15-50% ethylacetate/hexanes.

EXAMPLE 83B

This example was prepared by substituting EXAMPLE 83A for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 83C

This example was prepared by substituting EXAMPLE 83B for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 83D

This example was prepared by substituting EXAMPLE 83C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 83E

This example was made by substituting EXAMPLE 837538C and EXAMPLE 83Dfor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (br s,1H), 9.46 (br s, ¹H), 9.36 (br s, 1H), 8.52 (d, 1H), 8.28 (d, 1H), 7.88(dd, 1H), 7.79 (d, 2H), 7.41 (d, 2H), 7.35 (d, 2H), 7.17 (m, 4H), 7.09(m, 2H), 6.96 (d, 2H), 4.67 (m, 1H), 3.89 (br s, 2H), 3.75 (m, 4H), 3.43(m, 2H), 3.36 (m, 4H), 3.16 (br s, 2H), 2.82 (s, 3H), 2.75 (s, 3H), 2.26(br s, 2H), 2.21 (br s, 2H), 1.71 (br s, 4H).

EXAMPLE 84

This example was made by substituting EXAMPLE 83D for4-((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (br s, 1H), 9.94 (br s,1H), 9.42 (br s, 1H), 8.51 (d, 1H), 8.28 (d, 1H), 7.87 (dd, 1H), 7.78(d, 2H), 7.73 (br s, 1H), 7.52 (d, 4H), 7.39 (d, 2H), 7.34 (m, 2H), 7.17(m, 2H), 7.09 (m, 3H), 6.93 (d, 2H), 4.66 (m, 1H), 4.29 (br s, 2H), 3.85(br s, 2H), 3.75 (t, 2H), 3.43 (d, 2H), 3.36 (m, 2H), 3.12 (br s, 4H),2.87 (br s, 3H), 2.82 (s, 3H).

EXAMPLE 85A

This example was prepared by substituting diethylamine for dimethylaminein EXAMPLE 83A.

EXAMPLE 85B

This example was prepared by substituting EXAMPLE 85A for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 85C

This example was prepared by substituting EXAMPLE 85B for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 85D

This example was prepared by substituting EXAMPLE 85C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 85E

This example was made by substituting EXAMPLE 85D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (br s, 1H), 9.99 (br s,1H), 9.02 (br s, 1H), 8.51 (d, 1H), 8.33 (d, 1H), 7.87 (dd, 1H), 7.77(d, 2H), 7.74 (br s, 1H), 7.52 (d, 4H), 7.39 (d, 2H), 7.33 (m, 2H), 7.18(m, 2H), 7.10 (m, 3H), 6.93 (d, 2H), 4.60 (m, 1H), 4.26 (br s, 2H), 3.85(br s, 2H), 3.43 (m, 2H), 3.36 (dd, 2H), 3.15 (m, 6H), 2.92 (br s, 4H),1.19 (m, 6H).

EXAMPLE 86A

This example was prepared by substituting morpholine for dimethylaminein EXAMPLE 83A.

EXAMPLE 86B

This example was prepared by substituting EXAMPLE 86A for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 86C

This example was prepared by substituting EXAMPLE 86B for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 86D

This example was prepared by substituting EXAMPLE 86C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 86E

This example was made by substituting EXAMPLE 86D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (br s, 1H), 9.95 (br s,1H), 8.51 (d, 1H), 8.33 (d, 1H), 7.86 (dd, 1H), 7.78 (d, 2H), 7.74 (brs, 1H), 7.52 (d, 4H), 7.39 (d, 2H), 7.34 (m, 1H), 7.25 (d, 1H), 7.19 (m,2H), 7.09 (m, 3H), 6.93 (d, 2H), 4.59 (br s, 1H), 4.29 (br s, 2H), 3.39(m, 4H), 3.12 (br s, 6H), 2.90 (br s, 3H).

EXAMPLE 87

This example was made by substituting EXAMPLE 837538C and EXAMPLE 85Dfor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (br s,1H), 9.67 (br s, 1H), 9.06 (br s, 1H), 8.52 (d, 1H), 8.33 (d, 1H), 7.87(dd, 1H), 7.79 (d, 2H), 7.41 (d, 2H), 7.33 (d, 1H), 7.17 (m, 4H), 7.10(m, 3H), 6.96 (d, 2H), 4.61 (m, 1H), 3.88 (br s, 2H), 3.76 (m, 4H), 3.59(br s, 2H), 3.42 (m, 2H), 3.15 (m, 4H), 2.80 (br s, 2H), 2.27 (br s,2H), 2.22 (br s, 2H), 1.71 (br s, 4H), 1.19 (dd, 6H).

EXAMPLE 88

This example was made by substituting EXAMPLE 837538C and EXAMPLE 86Dfor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (br s,1H), 9.97 (br s, 1H), 9.55 (br s, 1H), 8.51 (d, 1H), 8.38 (d, 1H), 7.86(dd, 1H), 7.79 (d, 2H), 7.41 (d, 2H), 7.25 (d, 1H), 7.17 (m, 5H), 7.09(m, 2H), 6.96 (d, 2H), 4.58 (m, 1H), 3.90 (br s, 2H), 3.39 (m, 4H), 3.17(br s, 4H), 2.80 (br s, 2H), 2.26 (br s, 2H), 2.22 (br s, 2H), 1.71 (brs, 4H).

EXAMPLE 89

A mixture of EXAMPLE 833566 (44.9 mg) and 2.47 mmol/g MP-BH₃CN (0.81 g)in 1:1 dichloromethane/methanol at 25° C. (4 mL) was treated with DIEAand acetic acid to pH 5-6, shaken for 18 hours, filtered, andconcentrated. The concentrate was chromatographed on C-18 with 30-100%acetonitrile/water/0.1% TFA. ¹H NMR (500 MHz, DMSO-d₆) δ 12.13 (br s,1H), 9.76 (br s, 1H), 9.18 (br s, 1H), 8.54 (d, 1H), 8.32 (d, 1H), 7.87(dd, 1H), 7.78 (d, 2H), 7.71 (br s, 1H), 7.53 (m, 4H), 7.41 (d, 2H),7.34 (m, 1H), 7.23 (m, 3H), 7.14 (m, 3H), 6.93 (d, 2H), 4.33 (br s, 2H),4.22 (m, 1H), 3.85 (br s, 2H), 3.12 (m, 4H), 2.82 (s, 3H), 2.19 (m, 2H),0.81 (m, 4H).

EXAMPLE 90A

A mixture of magnesium turnings (0.144 g) and one iodine crystal at 25°C. was treated with 2-phenylbenzyl bromide (1.48 g) in diethyl ether (10mL), stirred for 3 hours, cooled to 0° C., treated with4-(4-oxo-piperidine-1-yl)benzoic acid ethyl ester, prepared as describedin J. Het. Chem. 1969, 6, 941, (1.48 g) in diethyl ether (5 mL) and THF(5 mL), stirred at 25° C. for 18 hours, and treated with ethyl acetateand aqueous NH₄Cl. The extract was extracted with ethyl acetate, and thecombined extracts were dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 25% ethylacetate/hexane.

EXAMPLE 90B

EXAMPLE 90A (0.27 g) in THF (10 mL) at 25° C. was treated with 60% oilyNaH (0.24 g), stirred for 2 hours at 50° C., treated with HMPA (2 mL)and methyl iodide (2 mL), heated at reflux for 18 hours, cooled to 0°C., and treated with ethyl acetate and aqueous NaHSO₄. The extract wasextracted with ethyl acetate, and the combined extracts were dried(Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 10% ethyl acetate/hexanes.

EXAMPLE 90C

A mixture of EXAMPLE 90B (0.09 g) and 1M LiOH (1 mL) in dioxane (5 mL)at 60° C. was stirred for 18 hours, and concentrated. The concentrate inwater was treated with 2M HCl and filtered.

EXAMPLE 90D

This example was made by substituting EXAMPLE 90C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (br s, 1H), 9.38 (s, 1H),8.54 (d, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.70 (d, 2H), 7.30 (m, 10H),7.15 (m, 4H), 6.82 (d, 2H), 4.19 (m, 1H), 3.45 (m, 4H), 3.13 (m, 2H),3.04 (s, 3H), 2.88 (m, 4H), 2.74 (d, 6H), 2.14 (q, 2H), 1.47 (m, 2H),1.18 (m, 2H).

EXAMPLE 91A

A mixture of magnesium turnings (0.432 g) and one iodide crystal at 25°C. was treated with 2-bromobenzyl bromide (4.5 g) in diethyl ether (30mL), stirred for 3 hours, cooled to 0° C., treated with4-(4-oxo-piperidine-1-yl)benzoic acid ethyl ester, prepared as describedin J. Het. Chem. 1969, 6, 941, (3.7 g) in diethyl ether (20 mL) and THF(10 mL), stirred at 25° C. for 18 hours, and treated with ethyl acetateand aqueous NH₄Cl. The extract was extracted with ethyl acetate, and thecombined extracts were dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 50% ethylacetate/hexane.

EXAMPLE 91B

EXAMPLE 91A (1.6 g) in THF (20 mL) at 25° C. was treated with 60% oilyNaH (0.288 g), stirred for 2 hours at 50° C., treated with HMPA (3 mL)and methyl iodide (3 mL), stirred at reflux for 18 hours, cooled to 0°C., and treated with ethyl acetate and aqueous NaHSO₄. The extract wasextracted with ethyl acetate, and the combined extracts were dried(Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 10-15% ethyl acetate/hexanes.

EXAMPLE 91C

A mixture of EXAMPLE 91B (0.6 g) and 1M LiOH (5 mL) in dioxane (5 mL) at60° C. was stirred for 18 hours and concentrated. The concentrate inwater was treated with 2M HC, and filtered.

EXAMPLE 91D

This example was made by substituting EXAMPLE 91C for EXAMPLE 2C inEXAMPLE 2D.

EXAMPLE 91E

A mixture of EXAMPLE 91D (0.08 g), 3-pyridineboronic acid (0.04 g),Pd(dppf)₂Cl₂ (0.01 g),and Cs₂CO₃ (0.1 g) in DMF (1 mL) at 80° C. wasstirred for 2 days and treated with ethyl acetate and brine. The extractwas extracted with ethyl acetate, and the extracts were combined anddried (Na₂SO₄), filtered, and concentrated. The concentrate was purifiedby high pressure liquid chromatography on a Waters Symmetry C₈ column(25 mm×100 mm, 7 μm particle size) with 10-100% acetonitrile/0.1%aqueous TFA over 8 minutes at a flow rate of 40 mL/minute. ¹H NMR (400MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.64 (d, 2H), 8.54 (d, 1H), 8.28 (d, 1H),7.97 (dd, 1H), 7.86 (dd, 1H), 7.70 (d, 2H), 7.62 (m, 1H), 7.37 (m, 3H),7.23 (m, 3H), 7.13 (m, 4H), 6.83 (d, 2H), 4.19 (m, 1H), 3.45 (m, 2H),3.39 (d, 2H), 3.13 (m, 2H),2.99 (s, 3H), 2.88 (m, 4H), 2.74 (d, 6H),2.14 (q, 2H), 1.49 (d, 2H), 1.20 (dt, 2H).

EXAMPLE 92

This example was prepared by substituting 4-pyridineboronic acid for4-pyridineboronic acid in EXAMPLE 91. ¹H NMR (400 MHz, DMSO-d₆) δ 9.47(br s, 1H), 8.75 (d, 2H), 8.53 (d, 1H), 8.28 (d, 1H), 7.86 (dd, 1H),7.70 (d, 2H), 7.66 (d, 2H), 7.39 (m, 3H), 7.23 (d, 2H), 7.13 (m, 4H),6.83 (d, 2H), 4.18 (m, 1H), 3.46 (m, 2H), 3.39 (d, 2H), 3.13 (m,2H),2.99 (s, 3H), 2.86 (m, 4H), 2.74 (d, 6H), 2.14 (q, 2H), 1.49 (d,2H), 1.20 (dt, 2H).

EXAMPLE 93

This example was prepared by substituting thiophene-2-boronic acid for4-pyridineboronic acid in EXAMPLE 91. NMR (400 MHz, DMSO-d₆) δ 8.44 (d,1H), 8.26 (d, 1H), 7.79 (dd, 1H), 7.67 (d, 2H), 7.57 (dd, 1H), 7.3 (m, 8H), 7.17 (d, 1H), 7.10 (m, 2H), 6.87 (d, 1H),6.71 (d, 2H), 4.05 (m, 1H),3.30 (m, 4H), 3.12 (s, 3H), 3.03 (s, 2H), 2.74 (m, 4H), 2.43 (s, 6H),2.00 (m, 2H), 1.55 (d, 2H), 1.30 (dt, 2H).

EXAMPLE 94

This example was prepared by substituting thiophene-3-boronic acid for4-pyridineboronic acid in EXAMPLE 91. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44(d, 1H), 8.26 (d, 1H), 7.79 (dd, 1H), 7.67 (d, 2H), 7.59 (m, 1H), 7.44(m, 1H), 7.28 (m, 7H),.7.16 (m, 2H), 6.87 (d, 1H),6.71 (d, 2H), 4.05 (m,1H), 3.30 (m, 4H), 3.07 (s, 3H), 2.94 (s, 2H), 2.74 (m, 4H), 2.45 (s,6H), 2.00 (m, 2H), 1.49 (d, 2H), 1.25 (dt, 2H).

EXAMPLE 95A

N-methyl-2,2,2-trifluoroacetamide (6.35 g) in diethyl ether (25 mL) at−15° C. was treated with lithium aluminum hydride (3.8 g) in diethylether (25 mL) over 1 hour, stirred for 2 hours, stirred at 25° C. for 16hours, cooled to 0° C., treated with water, and distillated at 34-36° C.The distillate was treated with HCl and filtered.

EXAMPLE 95B

This example was made by substituting EXAMPLE 95A for isopropylamine inEXAMPLE 28. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, 1H), 8.52 (d, 1H), 7.83(dd, 1H), 7.74 (d, 2H), 7.52 (d, 1H), 7.47 (m, 4H), 7.38 (m, 2H), 7.24(m, 2H), 7.14 (m, 4H), 6.82 (d, 2H), 4.46 (m, 1H), 4.12 (q, 2H), 3.35(m, 10H), 3.04 (s, 3H), 2.42 (m, 4H).

EXAMPLE 96A

This example was made by substituting 2,2,2-trifluoroethylamine forisopropylamine in EXAMPLE 28.

EXAMPLE 96

Borane.dimethyl sulfide (0.37 mL) was treated with EXAMPLE 96A (110 mg)in THF (2 mL) at 25° C., for 5 hours, treated with methanol, andconcentrated. The concentrate was purified by HPLC with 0-70%acetonitrile/water/0.1% TFA. ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (d, 1H),8.30 (d, 1H), 7.84 (dd, 1H), 7.76 (d, 2H), 7.52 (m, 3H), 7.35 (m, 4H),7.15 (m, 6H), 6.92 (d, 2H), 4.46 (m, 1H), 3.75 (m, 2H), 3.5 (m, 12H),2.42 (m, 4H).

EXAMPLE 97A

This example was made by substituting methyl trifluoroacetamide forEXAMPLE 100A in EXAMPLE 100B.

EXAMPLE 97B

This example was made by substituting EXAMPLE 97A and EXAMPLE 30A forisopropylamine and EXAMPLE 27E in EXAMPLE 28.

EXAMPLE 97C

This example was made by substituting EXAMPLE 97C for EXAMPLE 96A inEXAMPLE 96.

EXAMPLE 97D

This example was made by substituting EXAMPLE 97C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (d, 1H), 8.59 (d, 1H),7.99 (dd, 1H), 7.95 (d, 2H), 7.71 (m, 3H), 7.55 (m, 3H), 7.41 (d, 2H),7.29 (m, 5H), 7.11 (d, 2H), 4.46 (br s, 1H), 4.33 (m, 1H), 3.75 (m,12H), 3.31 (q, 2H), 2.78 (m, 2H), 2.68 (s, 3H), 2.09 (m, 2H).

EXAMPLE 98

This example was made by substituting EXAMPLE 32D and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹ _(H NMR ()400 MHz, DMSO-d₆) δ 9.71 (s,1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.69 (d, 2H), 7.46 (d,2H), 7.30 (m, 7H), 7.14 (m, 4H), 6.82 (d, 2H), 4.18 (m, 1H), 3.95(m,2H), 3.67 (m, 4H), 3.39 (m, 4H), 3.19 (m, 2H), 3.03 (s, 3H), 3.00 (m,2H), 2.85 (m, 4H), 2.17 (m, 2H), 1.47 (d, 2H), 1.17 (t, 2H).

EXAMPLE 99

This example was made by substituting EXAMPLE 32D and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (t, 1H),8.53 (d, 1H), 7.90 (dd, 1H), 7.68 (d, 2H), 7.46 (d, 2H), 7.46 (m, 3H),7.28 (m, 6H), 7.16 (m, 3H), 6.81 (d, 2H), 3.66 (q, 2H) 3.41 (m, 2H),3.03 (s, 3H), 2.48 (m, 4H), 1.47 (m, 2H), 1.18 (dt, 2H).

EXAMPLE 100A

Trifluoroacetic anhydride (15 g) in diethyl ether (80 mL) at −10° C. wastreated with ethylamine for 40 minutes and distilled under vacuum at 68°C.

EXAMPLE 100B

EXAMPLE 100A (7.8 g) in diethyl ether (25 mL) at −15° C. was treatedwith lithium aluminum hydride (4.17 g) in diethyl ether (25 mL) over 1hour, stirred for 2 hours then at 25° C. for 16 hours, cooled to 0° C.,treated with water (10 mL), 15% NaOH (10 mL), and water (30 mL), stirreda for 30 minutes, and filtered. The filtrate was washed with water andbrine, dried (Na₂SO₄), and filtered. The filtrate was treated with HCl,and filtered.

EXAMPLE 100C

This example was made by substituting EXAMPLE 100B and EXAMPLE 30A forisopropylamine and EXAMPLE 27E in EXAMPLE 28.

EXAMPLE 100D

This example was made by substituting EXAMPLE 100C for EXAMPLE 96A inEXAMPLE 96.

EXAMPLE 100E

This example was made by substituting EXAMPLE 100D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (br s, 1H), 8.51 (d,1H), 8.32 (d, 1H), 7.80 (dd, 1H), 7.74 (d, 2H), 7.46 (m, 5H), 7.37 (m,2H), 7.24 (d, 2H), 7.12 (m, 3H), 7.02 (d, 1H), 6.89 (d, 2H), 4.12 (m,1H), 3.42 (s, 2H), 3.35 (m, 6H), 3.13 (q, 2H), 2.63 (t, 2H), 2.56 (q,2H), 2.40 (s, 4H), 1.90 (m, 2H), 0.88 (t, 3H).

EXAMPLE 101

This example was made by substituting 2-fluoroethylamine forisopropylamine in EXAMPLE 35B. ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 2H),8.53 (d, 1H), 8.26 (d, 1H), 7.86 (dd, 1H), 7.75 (m, 3H), 7.52 (m, 4H),7.38 (d, 2H), 7.33 (m, 1H), 7.15 (m, 5H), 6.92 (d, 2H), 4.71 (t, 1H),4.61 (t, 1H), 4.30 (m, 2H), 4.21 (m, 1H), 3.38 (d, 2H), 3.25 (m, 12H),2.11 (m, 2H).

EXAMPLE 102

This example was made by substituting 2,2-difluoroethylamine forisopropylamine in EXAMPLE 35B. ₁H NMR (400 MHz, DMSO-d₆) δ 9.15 (s, 2H),8.53 (d, 1H), 8.26 (d, 1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.74 (m, 1H),7.52 (m, 4H), 7.38 (d, 2H), 7.33 (m, 1H), 7.15 (m, 5H), 6.92 (d, 2H),6.36 (tt, 1H), 4.23 (m, 1H), 4.00 (m, 4H), 3.49 (t, 2H), 4.39 (d, 2H),3.10 (m, 4H), 2.90 (m, 2H), 2.54 (s, 2H), 2.13 (m, 2H).

EXAMPLE 103A

A mixture of EXAMPLE 2 (250 mg) and 10% Pd on carbon (100 mg) inmethanol (5 mL) and ethyl acetate (5 mL) at 25° C. was stirred under H₂(balloon) for 18 hours, filtered through diatomaceous earth (Celite®),and concentrated.

EXAMPLE 103B

A mixture of EXAMPLE 103A (0.06 g) in 80% formic acid (3 mL) at 100° C.was stirred for 3 hours and concentrated. The concentrate was purifiedby high pressure liquid chromatography on a Waters Symmetry C₈ column(25 mm×100 mm, 7 μm particle size) with 10-100% acetonitrile/0.1%aqueous TFA over 8 minutes at a flow rate of 40 mL/minute. ¹H NMR (400MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.64 (s, 1H)., 8.56 (s, 1H), 8.22 (s,1H), 7.83 (d, 1H), 7.75 (m, 4H), 7.52 (m, 4H), 7.40 (d, 2H), 7.33 (m,1H), 7.14 (m, 3H), 7.07 (m, 1H), 6.92 (d, 2H), 4.76 (m, 1H), 3.85 (m,6H), 3.66 (d, 2H), 3.15 (m, 4H), 2.71 (s, 6H), 2.45 (m, 2H).

EXAMPLE 104

A mixture of EXAMPLE 103A (0.06 g) and 12M HCl (0.56 mL) in acetic acid(2 mL) at 0° C. was treated with NaNO₂ (7.2 mg) in water (0.38 mL),stirred for 2 hours, and concentrated. The concentrate was purified byhigh pressure liquid chromatography on a Waters Symmetry C₈ column (25mm×100 mm, 7 μm particle size) with 10-100% acetonitrile/0.1% aqueousTFA over 8 minutes at a flow rate of 40 mL/minute. ¹H NMR (400 MHz,DMSO-d₆) δ 9.50 (s, ¹H), 8.57 (s, 1H), 8.06 (d, 1H), 7.99 (d, 1H), 7.77(d, 2H), 7.74 (m, 1H), 7.52 (m, 4H), 7.40 (d, 2H), 7.33 (m, 1H), 7.04(m, 5H), 6.92 (d, 2H), 5.24 (m, 1H), 3.74 (m, 2H), 3.45 (m, 6H), 3.15(m, 4H), 2.71 (s, 6H).

EXAMPLE 105A

3-Cyano-4-fluorobenzenesulfonyl chloride (5 g) in dichloromethane (110mL) at −78° C. was treated with 7M NH₃ in methanol (8.1 mL), stirred at−20° C., and acidified with 1M HCl. The water layer was separated andextracted with dichloromethane. The extract was dried (MgSO₄), filtered,and concentrated. The concentrate was recrystallized from hexane/ethylacetate.

EXAMPLE 105B

This example was made by substituting EXAMPLE 18C with EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 105B

A mixture of EXAMPLE 105A (0.5 g), EXAMPLE 105B (0.5 g), and DIEA (0.8mL) in THF (6 mL) at 80° C. was stirred for 16 hours and concentrated.The concentrate was flash chromatographed on silica gel with 5%methanol/dichloromethane.

EXAMPLE 105C

A mixture of EXAMPLE 105B (0.05 g) and KOH (0.031 g) in tert-butanol (2mL) at reflux was stirred for 6 hours and concentrated. The concentratewas flash chromatographed on silica gel with 5-10%methanol/dichloromethane.

EXAMPLE 105D

This example was made by substituting EXAMPLE 105C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 9.63 (s, 1H),8.82 (d, 1H), 8.15 (s, 1H), 7.76 (d, 2H), 7.70 (d, 1H), 7.52 (d, 4H),7.39 (d, 2H), 7.33 (m, 2H), 7.27 (m,. 2H), 7.19 (m, 1H), 6.92 (d, 2H),6.69 (s, 1H), 4.14 (m, 1H), 3.86 (m, 2H), 3.45 (m, 6H), 3.15 (m, 4H),2.74 (s, 6H), 2.10 (m, 1H), 1.96 (m, 1H).

EXAMPLE 106B

A mixture of EXAMPLE 1A (1.5 g), 2-bromobenzoyl chloride (1.5 g), andDIEA (2 mL) in THF (20 mL) at 25° C. was stirred for 16 hours, filtered,and concentrated.

EXAMPLE 106C

EXAMPLE 106B (0.3 g), 4-(N,N-dimethylamino)phenylboronic acid (0.146 g),PdCl₂(PPh₃)₄ (0.03 g), and 2M Na₂CO₃ (0.4 mL) in 7:3:2 DME/water/ethanol(3 mL) at 150° C. in a 10 mL microwave reaction tube was stirred in amicrowave reactor for 20 minutes, filtered through diatomaceous earth(Celite®) and concentrated. The concentrate was flash chromatographed onsilica gel with 5-50% ethyl acetate/hexanes.

EXAMPLE 106D

This example was made by substituting EXAMPLE 106C for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 106E

This example was made by substituting EXAMPLE 106D for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.29 (s, 1H),8.53 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.30 (m, 11H), 6.80 (d, 2H),6.73 (d, 2H), 4.18 (m, 1H), 3.50 (m, 4H), 3.39 (m, 4H), 3.04 (m, 6H),2.78 (s, 6H), 2.74 (d, 6H), 2.14 (m, 2H).

EXAMPLE 107A

This example was prepared by substituting4-(methylsulfanyl)phenylboronic acid for4-(N,N-dimethylamino)phenylboronic acid in EXAMPLE 106C.

EXAMPLE 107B

This example was made by substituting EXAMPLE 107A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 107C

This example was made by substituting EXAMPLE 107B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.38 (s, 1H),8.53 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.49 (m, 3H), 7.33 (m,5H),7.17 (m, 5H), 6.83 (d, 2H), 4.18 (m, 1H), 3.65 (m, 2H), 3.39 (m,4H), 3.11 (m, 4H), 2.97 (m, 1H), 2.85 (m, 1H), 2.73 (d, 6H), 2.39 (s,3H), 2.14 (m, 2H).

EXAMPLE 108A

This example was prepared by substituting 4-chlorophenylboronic acid for4-(N,N-dimethylamino)phenylboronic acid in EXAMPLE 106C.

EXAMPLE 108B

This example was made by substituting EXAMPLE 108A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 108C

This example was made by substituting EXAMPLE 108B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.38 (s, 1H),8.53 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.74 (d, 2H), 7.49 (m, 8H),7.17 (m, 5H), 6.83 (d, 2H), 4.18 (m, 1H), 3.65 (m, 2H), 3.39 (m, 4H),3.11 (m, 4H), 2.99 (m, 1H), 2.89 (m, 1H), 2.74 (d, 6H), 2.14 (m, 2H).

EXAMPLE 109

This example was made by substituting EXAMPLE 105B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 9.60 (s, 1H),7.68 (d, 1H), 7.52 (d, 2H), 7.27 (m, 43H), 7.14 (d, 2H), 7.08 (m, 1H),7.00 (m, 5H), 6.91 (m, 1H), 6.67 (d, 2H), 6.37 (m, 2H), 3.96 (m, 1H),3.70 (m, 2H), 3.80 (m, 4H),3.02 (m, 4H), 2.89 (m, 4H), 2,58 (s, 6H),1.84 (m, 2H).

EXAMPLE 110A

3,4-dihydroxy-butyric acid methyl ester, prepared as described in Chem.Lett., 1984, 1389, (510 mg) in dimethylamine in THF (19 mL) in a sealedtube at 80° C. was stirred for 12 hours and concentrated. Theconcentrate was flash chromatographed on silica gel with 0-20%methanol/dichloromethane.

EXAMPLE 110B

A mixture of EXAMPLE 110A (200 mg), benzenethiol (153 μL), andtributylphosphine (372 μL) in THF (10 mL) at 0° C. was treated with1,1′-(azodicarbonyl)dipiperidine (377 mg), stirred at 25° C. for 12hours, and treated with ethyl acetate and 1M NaOH. The extract wasextracted with ethyl acetate, and the extract was dried (MgSO₄),filtered and concentrated. The concentrate was flash chromatographed onsilica gel with 0% to 80% ethyl acetate/dichloromethane.

EXAMPLE 110C

EXAMPLE 110B (160 mg) in THF (2.3 mL) at 25° C. was treated withborane.THF (1 mL), stirred for 5 hours, treated with saturatedmethanolic HCl (3 mL), heated at reflux for 2 hours, and concentrated.The concentrate was flash chromatographed on silica gel with 0-10%NH₃-saturated methanol (saturated NH₃)/dichloromethane.

EXAMPLE 110D

EXAMPLE 110C (224 mg) in DMF (1 mL) at 0° C. was treated with NaH (40mg), stirred at 25° C. for 1 hour, cooled to 0° C., treated with15-crown-5 (146 μL), stirred for 15 minutes, treated with4-fluoro-3-nitrobenzenesulfonamide, prepared as described in WO02/24636,(110 mg), stirred at 25° C. for 2 hours, treated with saturated NH₄Cl(200 μL), and concentrated. The concentrate was flash chromatographed onsilica gel with 50-100% ethyl acetate/hexane then switching to 0-10%NH₃-saturated methanol/dichloromethane.

EXAMPLE 110E

This example was made by substituting EXAMPLE 110D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ9.70 (s, 1H), 8.38 (d, 1H),8.09 (dd, 1H), 7.78 (m, 3H), 7.51 (m, 5H), 7.27 (m, 8H), 6.92 (d, 2H),5.01 (m, 1H), 3.47 (m, 2H), 3.33 (m, 2H), 3.21 (m, 4H), 3.14 (m, 2H),3.05 (s, 2H), 2.76 (s, 6H), 2.23 (m, 2H).

EXAMPLE 111

This example was made by substituting4,4-dimethyl-4,5-dihydro-1H-imidazole for isopropylamine in EXAMPLE 35B.¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.54 (d, 1H),8.29 (s, 1H),7.86 (dd, 1H), 7.76 (d, 2H),7.65 (m, 2H), 7.46 (m, 5H), 7.30 (m, 1H),7.22 (d, 2H), 7.12 (m, 4H), 6.92 (d, 2H), 4.14 (m, 1H), 3.54 (m, 4H),3.40 (m, 10H), 2.18 (m, 2H), 1.32 (s, 6H), 0.87 (m, 2H).

EXAMPLE 112

This example was made by substituting 1,4,5,6-tetrahydro-pyrimidine forisopropylamine in EXAMPLE 35B. H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H),9.62 (d, 1H), 8.53 (d, 1H), 8.27 (d, 1H), 8.02 (d, 1H), 7.85 (dd, 1H),7.76 (d, 2H),7.51 (m, 3H), 7.40 (m, 1H), 7.14 (m, 7H), 6.93 (d, 2H),4.14 (m, 1H), 3.40 (m, 14H),3.19 (m, 2H), 2.12 (m, 2H), 1.88 (m, 2H).

EXAMPLE 113

This example was made by substituting 2-methyl-4,5-dihydro-1H-imidazolefor isopropylamine in EXAMPLE 35B. ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s,1H), 8.56 (d, 1H), 8.32 (d, 1H), 7.90 (dd, 1H), 7.81 (d, 2H),7.55 (m,4H), 7.43 (d, 2H), 7.37 (m, 1H), 7.26 (m, 3H), 7.14 (m, 3H), 6.97 (d,2H), 4.28 (m, 2H), 3.85 (m, 14H),3.42 (m, 2H), 2.14 (m, 2H), 2.08 (s,3H), 1.27 (m, 2H).

EXAMPLE 114

This example was made by substituting EXAMPLE 842657F and1,4,5,6-tetrahydro-pyrimidine for isopropylamine and 35A in EXAMPLE 35B.¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 9.60 (s, 1H), 8.01 (d, 1H),7.95 (d, 1H), 7.80 (dd, 1H), 7.73 (d, 2H),7.68 (m, 1H), 7.49 (m, 3H),7.41 (d, 2H), 7.27 (m, 5H), 7.17 (m, 1H), 6.90 (d, 2H), 6.82 (d, 1H),6.00 (d, 1H), 3.83 (m, 2H), 3.40 (m, 16H), 2.08 (m, 2H), 1.285 (t, 2H).

EXAMPLE 115

This example was made by substituting2,4-dimethyl-4,5-dihydro-1H-imidazole for 1,4,5,6-tetrahydro-pyrimidineIn EXAMPLE 114. ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 10.02 (s,1H), 7.95 (d, 1H), 7.82 (dd, 1H), 7.73 (d, 2H),7.70 (m, 1H), 7.50 (m,3H), 7.40 (d, 2H), 7.27 (m, 5H), 6.92 (m, 3H), 6.04 (d, 1H), 4.08 (m,2H), 3.90 (m, 4H), 3.40 (m, 10H), 2.04 (m, 2H), 2.02 (s, 3H), 1.10 (m,3H).

EXAMPLE 116

This example was made by substituting 2-methyl-4,5-dihydro-1H-imidazolefor 1,4,5,6-tetrahydro-pyrimidine In EXAMPLE 114. ¹H NMR (400 MHz,DMSO-d₆) δ 11.92 (s, 1H), 9.82 (s, 1H), 7.88 (d, 1H), 7.75 (dd,. 1H),7.68 (d, 2H),7.62 (m, 1H), 7.43 (m, 3H), 7.35 (d, 2H), 7.28 (m, 5H),6.82 (m, 3H), 5.98 (d, 1H), 3.90 (m, 2H), 3.70 (m, 4H), 3.40 (m, 12H),2.00 (m, 2H), 1.95 (s, 3H).

EXAMPLE 117

This example was made by substituting4,4-dimethyl-4,5-dihydro-1H-imidazole for 1,4,5,6-tetrahydro-pyrimidineIn EXAMPLE 114. ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 10.22 (s,1H),8.25 (d, 1H), 7.95 (d, 1H), 7.80 (dd, 1H), 7.75 (d, 2H),7.65 (m,1H), 7.52 (m, 3H), 7.50 (d, 2H), 7.25 (m, 5H), 7.18 (m, 1H), 6.90 (d,2H), 6.82 (d, 1H), 6.00 (d, 1H), 3.88 (m, 2H), 3.50 (m, 4H), 3.40 (m,10H), 2.08 (m, 2H), 1.25 (m, 6H).

EXAMPLE 118A

EXAMPLE 18D (200 mg), cesium carbonate (671 mg) and tetrabutylammoniumiodide (61 mg) in DMF (4 mL) at 25° C. was treated with 4-methoxybenzylchloride (246 μL), stirred for 12 hours, and treated with ethyl acetateand saturated NH₄Cl. The extract was extracted with ethyl acetate, andthe combined extracts were dried (MgSO₄), filtered, and concentrated.The concentrate was flash chromatographed on silica gel with 0-50% ethylacetate/hexane.

EXAMPLE 118B

EXAMPLE 110C (38 mg) in N-methyl-2-pyrrolidinone (845 μL) at 25° C. wastreated with NaH (8 mg), stirred for 20 minutes, treated with EXAMPLE118A (122 mg), stirred for 3 hours, treated with NaH (6.6 mg) andEXAMPLE 118A (76 mg), stirred for 3 hours, treated with saturatedNaHCO₃, (1 mL), and partitioned between ethyl acetate and saturatedNaHCO₃. The extract was extracted with ethyl acetate, and the combinedextracts were dried (MgSO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 0-to 50% acetonitrile (1%NH₃-saturated methanol)/1% NH₃-saturated ethyl acetate.

EXAMPLE 118C

EXAMPLE 118C (90 mg) in triethylsilane/TFA/dichloromethane (0.05 mL/0.45mL/0.5 mL) at 25° C. was stirred for 12 hours and concentrated. Theconcentrate was flash chromatographed on silica gel with 5%NH₃-saturated methanol/dichloromethane.

EXAMPLE 118D

This example was made by substituting EXAMPLE 118C and EXAMPLE 837538Cfor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide(prepared according to the procedure described in commonly ownedWO02/24636, filed Sep. 20, 2001) in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-₆)δ 12.02 (s, 1H), 9.40 (s, 1H),8.12 (d, 2H), 7.72 (d, 2H), 7.41 (m, 3H),7.31 (d, 2H),7.26 (m, 2H), 7.17 (m, 3H), 6.95 (d, 2H), 4.97 (m, 1H),3.50 (m, 12H), 3.16 (m, 4H), 2.76 (s, 6H), 2.23 (m, 4H), 1.70 (s, 4H).

EXAMPLE 119A

A mixture of 4-bromo-3-(trifluoromethyl)benzenesulfonamide (0.121 g),EXAMPLE 847124C (0.17 g) EDAC (0.153 g), and DMAP (0.098 g) indichloromethane (2 mL) at 25° C. was stirred for 16 hours, treated withethyl acetate, washed with saturated NH₄Cl solution and brine, and dried(Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 5% methanol/dichloromethane.

EXAMPLE 119B

A mixture of EXAMPLE 119A (0.1 g), EXAMPLE 105B (0.038 g), Pd₂(dba)₃(0.011 g), BINAP (0.009 g), Cs₂CO₃ (0.07 g) in toluene (1.5 mL) at 100°C. was stirred for 16 hours, filtered, and concentrated. The concentratewas purified by high pressure liquid chromatography on a Waters SymmetryC₈ column (25 mm×100 mm, 7 μm particle size) with 10-100%acetonitrile/0.1% aqueous TFA over 8 minutes at a flow rate of 40mL/minute. ¹H NMR (400 MHz, DMSO-d₅) δ 9.60 (s, 1H), 7.95 (d, 1H), 7.81(dd, 1H), 7.76 (d, 2H), 7.41 (d, 2H), 7.28 (m,4H), 7.12 (d, 2H), 6.94(d, 2H), 6.87 (d, 1H), 6.02 (d, 1H), 3.91 (m, 3H), 3.63 (m, 2H), 3.40(m, 2H), 3.28 (m, 2H), 3.15 (m, 4H), 3.00 (m, 2H), 2.73 (d, 6H), 2.46(m, 4H), 2.10 (m, 2H), 1.82 (m, 2H), 1.57 (m, 4H).

EXAMPLE 120

This example was made by substituting bis(2-methoxyethyl)amine forisopropylamine in EXAMPLE 35B. ¹H NMR (500 MHz, DMSO-d₆) δ 12.02 (s,1H), 9.50 (s, 1H), 8.54 (d, 1H),8.27 (d, 1H), 7.87 (dd, 1H), 7.77 (m,3H), 7.52 (m, 4H), 7.39 (d, 2H), 7.34 (m, 1H), 7.16 (m, 5H), 6.94 (d,2H), 4.32 (m, 1H), 4.20 (m, 2H), 3.61 (m, 4H), 3.39 (m, 2H), 3.30 (m,12), 3.23 (s, 6H), 2.17 (m, 2H).

EXAMPLE 121

This example was made by substituting bis(2-methoxyethyl)amine for1,4,5,6-tetrahydropyrimidine in EXAMPLE 114. ¹H NMR (500 MHz, DMSO-d₆) δ12.02 (s, 1H), 9.50 (s, 1H), 7.95 (d, 1H),7.83 (dd, 1H), 7.75 (m, 3H),7.53 (m, 4H), 7.39 (d, 2H), 7.34 (m, 5H), 7.16 (m, 1H), 6.94 (m, 2H),6.02 (d, 1H), 4.32 (m, 1H), 3.96 (m, 2H), 3.61 (m, 4H), 3.39 (m, 16H),3.23 (s, 6H), 2.17 (m, 2H).

EXAMPLE 122A

A mixture of EXAMPLE 29C (0.5 g) and diethylamine (4 mL) in THF (4 mL)at 25° C. was stirred for 2 hours and concentrated. The concentrate wasflash chromatographed on silica gel with 5% to 10%methanol/dichloromethane.

EXAMPLE 122B

This example was made by substituting EXAMPLE 122A for EXAMPLE 105BEXAMPLE 119B. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 9.60 (s, 1H),8.50 (s, 1H), 7.95 (d, 1H), 7.81 (dd, 1H), 7.76 (d, 2H), 7.41 (d, 2H),7.28 (m,4H), 7.12 (d, 2H), 6.94 (m, 3H), 6.12 (d, 1H), 4.02 (m, 1H),3.89 (m, 2H), 3.63 (m, 4H), 3.42 (m, 4H), 3.17 (m, 2H), 2.93 (m, 2H),2.79 (m, 2H), 2.46 (m, 4H), 2.10 (m, 2H), 1.82 (m, 2H), 1.57 (m, 4H),1.23 (m, 12H).

EXAMPLE 859948

This example was made by substituting 4,4-difluoropiperidine forisopropylamine in EXAMPLE 35B. ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s,1H),. 8.55 (d, 1H), 8.30 (d, 1H), 7.87 (dd, 1H), 7.77 (d, 2H),7.55 (m,4H), 7.40 (d, 2H), 7.39 (m, 1H), 7.24 (m, 3H), 7.13 (m, 3H), 6.93 (d,2H), 4.20 (m, 2H), 3.86 (m, 4H),3.42 (m, 4H), 3.17 (m, 8H), 2.28 (m,4H), 2.18 (m, 4H).

EXAMPLE 855996

This example was made by substituting 2-methylpyrrolidine forisopropylamine in EXAMPLE 35B. H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H),8.54 (d, 1H), 8.32 (d, 1H), 7.87 (dd, 1H), 7.77 (d, 2H),7.53 (m, 4H),7.39 (d, 2H), 7.36 (m, 1H), 7.23 (m, 3H), 7.14 (m, 3H), 6.94 (d, 2H),4.05 (m, 6H), 3.57 (m, 2H), 3.40 (m, 4H), 3.06 (m, 4H), 2.14 (m, 2H),1.93 (m, 2H), 1.57 (m, 2H), 1.27 (m, 3H).

EXAMPLE 123A

2.5 g/100 mL Rieke magnesium in diethyl ether (12.75 mL) at 25° C. wastreated with 1-bromo-3-methyl-2-butene (1.81 g), stirred for 1 hour,added to 2-methylpropane-2-sulfonic acid (2-benzyloxyethylidene)amide,prepared as described in J. Org. Chem. 2001, 26, 8772-8778, (1.85 g) intoluene (30 mL) at −78° C., and treated, at 25° C., with saturatedNH₄Cl, ethyl acetate, and water. The extract was washed with water andbrine and dried (MgSO₄), filtered, and concentrated. The concentrate wasflash chromatographed on silica gel with 10-20% acetone/hexanes.

EXAMPLE 123B

EXAMPLE 123A (1.01 g) in methanol (20 mL) at 25° C. was treated with 4MHCl in dioxane (8 mL), stirred for 10 minutes, treated with 10% Pd/C,stirred under H₂ (balloon) for 18 hours, filtered through diatomaceousearth (Celite®), and concentrated. The concentrate was mixed with 1:1 2MNa₂CO₃/chloroform (60 mL), treated with benzylchloroformate (0.58 mL)and benzyltriethylammonium chloride (catalytic), and stirred 3 hours.The extract was washed with water, dried (MgSO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 3:1-2:1 hexanes/ethyl acetate.

EXAMPLE 123C

A mixture of EXAMPLE 123B (0.52 g), diphenyldisulfide (0.40 g), andtributylphosphine (0.81 g) in toluene (15 mL) at 85° C. was stirred for18 hours, cooled to 25° C., and concentrated. The concentrate was flashchromatographed on silica gel with 20:1 then 10:1 and 5:1 hexanes/ethylacetate.

EXAMPLE 123D

EXAMPLE 123C (0.52 g) in 30% HBr in acetic acid (15 mL) at 25° C. wasstirred for 2 hours, poured into 5% HCl (75 mL), washed with ethylacetate, brought to pH 12 with 15% NaOH, and extracted with chloroform.The extract was dried (MgSO₄) and concentrated.

EXAMPLE 123E

This example was made by substituting EXAMPLE 123D for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 123F

This example was made by substituting EXAMPLE 123 E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz,

DMSO-d₆) δ 12.07 (s, 1H), 9.61 (s, 1H), 8.49 (d, 1H), 8.35 (d, 1H),7.64-7.96 (m, 4H), 7.41-7.60 (m, 5H), 7.24-7.40 (m, 4H), 7.01-7.20 (m,4H), 6.92 (d, 2H), 4.38 (m, 2H), 4.05 (m, 1H), 3.68-3.95 (m, 2H),3.21-3.65 (m, 1H), 2.96-3.25 (m, 2H), 2.61-2.95 (m, 2H), 1.17-1.50 (m,1H), 0.93 (d, 6H), 0.80 (t, 4H).

EXAMPLE 124

This example was made by substituting tert-butyl(5R)-5-((4-(aminosulfonyl)-2-nitrophenyl)amino)-6-(phenylsulfanyl)hexylcarbamate,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 11.96 (s, 1H), 8.51 (d, 1H),8.28 (d, 1H), 7.83 (dd, 1H), 7.74 (d, 2H), 7.49-7.56 (m, 3H), 7.44-7.49(m, 2H), 7.34-7.41 (m, 2H), 7.20-7.28 (m, 3H), 7.03-7.19 (m, 4H), 6.89(d, 2H), 6.66-6.77 (m, 1H), 3.95-4.12 (m, 1H), 3.41 (m, 1H), 3.17-3.27(m, 4H), 2.79-2.96 (m, 4H), 2.33-2.45 (m, 5H), 1.73 (m, 4H), 1.18-1.43(m, 9H).

EXAMPLE 125

EXAMPLE 124 (0.40 g) in dichloromethane (10 mL) was treated with 4M HClin dioxane (2 mL), stirred for 20 hours at 25° C., and concentrated togive the desired product as the hydrochloride salt. ¹H NMR (300 MHz,DMSO-d₆) δ 12.09 (s, 1H), 9.76 (s, 1H), 8.53 (d, 1H), 8.30 (d, 1H), 7.85(dd, 1H), 7.77 (d, 3H), 7.62 (m, 4H), 7.52 (d, 2H), 7.40 (d, 1H), 7.34(d, 2H), 7.18-7.26 (m, 3H), 7.03-7.18 (m, 2H), 6.93 (d, 2H), 4.33 (m,2H), 4.08 (m, 3H), 3.28-3.42 (m, 4H), 3.11 (m, 4H), 2.81-2.96 (m, 1H),2.64-2.81 (m, 4H), 1.66-1.85 (m, 2H), 1.43-1.58 (m, 2H), 1.24-1.43 (m,2H).

EXAMPLE 126

EXAMPLE 125 (0.075 g) in dichloromethane (7 mL) was treated with DIEA(0.055 g), cooled to 0° C., treated with methanesulfonylchloride (0.013g), stirred for 1 hour, and treated with water. The extract was washedwith water and brine, and dried (MgSO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 0-2.5% methanolin dichloromethane. ¹H NMR (300 MHz, DMSO-d₆) δ 12.00 (s, 1H), 8.52 (d,1H), 8.30 (d, 1H), 7.84 (dd, 1H), 7.74 (d, 2H), 7.43-7.57 (m, 1H), 7.47(s, 2H), 7.32-7.42 (m, 2H), 7.20-7.29 (m, 3H), 7.04-7.19 (m, 4H),6.84-6.94 (m, 3H), 3.98-4.16 (m, 1H), 3.16-3.48 (m, 7H), 2.85-2.95 (m,2H), 2.83 (s, 3H), 2.41 (m, 3H), 1.67-1.83 (m, 2H), 1.28-1.50 (m, 4H).

EXAMPLE 127

EXAMPLE 125 (0.065 g) in dichloromethane (7 mL) at 25° C. was treatedwith DIEA (0.048 g), cooled to 0° C., treated withtrimethylsilylisocyanate (0.011 g), stirred at 25° C. for 24 hours,treated with methanol (0.5 mL), and concentrated. The concentrate waspurified by reverse phase HPLC (C-18) with 10-100% acetonitrile/watercontaining 0.1% TFA. ¹H NMR (300 MHz, DMSO-d₆) δ 12.07 (s, 1H), 9.56 (s,1H), 8.52 (s, 1H), 8.31 (d, 1H), 7.84 (dd, 1H), 7.77 (d, 3H), 7.52 (m,3H), 7.28-7.44 (m, 3H), 7.03-7.27 (m, 6H), 6.93 (d, 2H), 5.80-5.93 (m,1H), 5.18-5.42 (m, 2H), 4.26-4.51 (m, 2H), 4.08 (m, 2H), 3.75-3.98 (m,2H), 2.99-3.20 (m, 3H), 2.79-2.98 (m, 4H), 1.63-1.89 (m, 2H), 1.24-1.44(m, 4H).

EXAMPLE 128A

A mixture of ethyl 4-fluorobenzoate (7.71 g),1-(tert-butoxycarbonyl)piperazine (9.31 g), potassium carbonate (13.8g), and 1-methyl-2-pyrrolidinone (20 mL) at 130° C. was stirred for 16hours, poured into water, and filtered. The filtrant was washed withwater and dried in a vacuum oven at 50° C. and 18 mmHg.

EXAMPLE 128B

This example was prepared by substituting EXAMPLE 128A for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 128C

This example was prepared by substituting EXAMPLE 128B for EXAMPLE 1C inEXAMPLE 1D.

EXAMPLE 128D

EXAMPLE 128C (3.7 g) in dichloromethane (10 mL) and 4M HCl in dioxane(10 mL) at 25° C. was stirred for 5 hours, concentrated, treated withdiethyl ether (20 mL), and filtered. The filtrant was washed withdiethyl ether and dried in a vacuum oven at 50° C. and 18 mm Hg.

EXAMPLE 128E

EXAMPLE 128D (110 mg) in dichloromethane (2 mL) at 25° C. was treatedwith 2-(methylsulfanyl)benzaldehyde (27 mg), N,N-DIEA (52 mg), andsodium triacetoxyborohydride (38 mg), stirred for 16 hours, andconcentrated. The concentrate was flash chromatographed on silica gelwith 10% methanol/dichloromethane. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d,1H), 8.36 (d, 1H), 7.78 (dd, 1H), 7.73 (d, 2H), 7.38-7.21 (m, 6H), 7.18(d, 1H), 7.1,8-7.10 (m, 2H), 6.87 (d, 1H), 6.80 (d, 2H), 4.10-4.01 (m,1H), 3.52 (s, 2H), 3.33 (d, 2H), 3.18 (t, 4H), 2.65-2.40 (m, 6H), 2.44(s, 3H), 2.27 (s, 6H), 2.07-1.82 (m, 2H).

EXAMPLE 129A

2-(methylsulfanyl)benzaldehyde (1 g) in dichloromethane (35 mL) wastreated with 70% 3-chloroperoxybenzoic acid (3.32 g), stirred for 75minutes, and concentrated. The concentrate was flash chromatographed onsilica gel with 1:1 ethyl acetate/hexanes.

EXAMPLE 129B

EXAMPLE 128D (110 mg) in dichloromethane (2 mL) was treated with EXAMPLE129A (33 mg), 3.45 mmol/g N,N-DIEA resin (116 mg), and sodiumtriacetoxyborohydride (38 mg), stirred at 25° C. for 16 hours, andconcentrated. The concentrate was flash chromatographed on silica gelwith 10% methanol/dichloromethane. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d,1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.81 (dd, 1H), 7.73 (d, 2H), 7.70 (td,1H), 7.61 (d, 2H), 7.32 (dd, 2H), 7.24 (tt, 2H), 7.17 (tt, 1H), 6.90 (d,1H), 6.82 (d, 2H), 4.11-4.01 (m, 1H), 3.93 (s, 2H), 3.42 (s, 3H), 3.33(d, 2H), 3.18 (t, 4H), 3.00-2.80 (m, 2H), 2.62-2.48 (m, 4H), 2.56 (s,6H), 2.13-1.98 (m, 2H).

EXAMPLE 130A

N-(tertbutoxycarbonyl)glycine methyl ester (5 g) in THF (60 mL) at 0° C.was treated with 1.4M methylmagnesium bromide in 3:1 toluene/THF (75.5mL), stirred at 25° C. for 16 hours, cooled to 0° C., treated withsaturated NH₄Cl, and extracted with ethyl acetate. The extract waswashed with brine and dried (Na₂SO₄), filtered, and concentrated.

EXAMPLE 130B

EXAMPLE 130A (1 g) in THF (27 mL) at 0° C. was treated with potassiumtert-butoxide (663 mg), stirred for 30 minutes, and concentrated. Theconcentrate was flash chromatographed on silica gel with 5%methanol/ethyl acetate.

EXAMPLE 130C

A mixture of EXAMPLE 130B (120 mg), 2-bromobenzaldehyde (289 mg), andsodium tert-butoxide (150 mg) in toluene (5 mL) in a sealable containerwas degassed/flushed with nitrogen three times and treated withdichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II).dichloromethane (82 mg). The container was sealed, and the mixturewas heated at 120° C. for 16 hours and concentrated. The concentrate wasflash chromatographed on silica gel with 50% ethyl acetate/hexanes.

EXAMPLE 130D

EXAMPLE 128C (4.02 g) in dioxane (7 mL) at 25° C. was treated with 4MHCl (7 mL), stirred for 16 hours, neutralized and extracted withdichloromethane. The extract was concentrated. The concentrate waschromatographed on C₁₈ with 1:1 acetonitrile/0.1% aqueous TFA.

EXAMPLE 130E

EXAMPLE 130C (50 mg) in dichloromethane (2 mL) and methanol (0.4 mL) at25° C. was treated with EXAMPLE 130D (130 mg) and 2.38 mmol/g MP-BH₃CN(118 mg), stirred for 16 hours, and concentrated. The concentrate wasflash chromatographed on silica gel with 20% methanol/dichloromethane.¹H NMR (300 MHz, DMSO-d₆) δ 8.42 (d, 1H), 8.26 (d, 1H), 7.79 (dd, 1H),7.74 (dd, 2H), 7.62-7.44 (m, 2H), 7.40-7.35 (m, 2H), 7.32 (d, 2H), 7.25(td, 2H), 7.17 (tt, 1H), 6.88 (d, 1H), 6.82 (t, 2H), 4.10-4.01 (m, 1H),3.78 (s, 2H), 3.49 (s, 2H), 3.34 (d, 2H), 3.23-3.14 (m, 6H), 2.90-2.62(m, 4H), 2.43 (s, 6H), 2.10-1.90 (m, 2H), 1.50 (s, 6H).

EXAMPLE 131A

A mixture of 2-bromobenzaldehyde (4 g), butylamine (1.58 g), and 4Asieves (3 g) in dichloromethane (75 mL) at 25° C. was stirred for 72hours, filtered and concentrated.

EXAMPLE 131B

EXAMPLE 131A (400 mg) in THF (5 mL) at 0° C. was treated with MnCl₂ (21mg) and 2M cyclohexylmagnesium chloride in THF (1.67 mL), stirred for 25minutes, treated with saturated NH₄Cl, and extracted with diethyl ether.The extract was washed with brine, dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 5% ethyl acetate/hexanes. Relevant fractions were combined andconcentrated. The concentrate in 1:1 1,4-dioxane/water was stirred at25° C. for 16 hours and extracted with diethyl ether. The extract waswashed with brine and dried (Na₂SO₄), filtered, and concentrated.

EXAMPLE 131C

This example was prepared by substituting EXAMPLE 131B for EXAMPLE 130Cin EXAMPLE 130D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (d, 1H), 8.18 (d, 1H),7.82 (dd, 1H), 7.73 (d, 2H), 7.45-7.37 (m, 1H), 7.30 (d, 2H), 7.28-7.07(m, 6H), 6.92 (d, 1H), 6.82 (d, 2H), 4.12-4.01 (m, 1H), 3.51 (s, 2H),3.33 (d, 2H), 3.17 (s, 4H), 3.05-2.88 (m, 3H), 2.70-2.52 (m, 2H), 2.61(s, 6H), 2.16-1.98 (m, 2H), 1.84-1.65 (m, 6H), 1.50-1.22 (m, 6H).

EXAMPLE 132

This example was prepared by substituting 2-morpholinobenzaldehyde forEXAMPLE 130C in EXAMPLE 130D. ¹ _(H NMR ()300 MHz, DMSO-d₆) δ 6 8.46 (d,1H), 8.22 (d, 1H), 7.81 (dd, 1H), 7.72 (d, 2H), 7.39 (dd, 1H), 7.32 (d,2H), 7.28-7.22 (m, 3H), 7.20-7.04 (m, 3H), 6.90 (d, 1H), 6.81 (d, 2H),4.14-4.00 (m, 1H), 3.75 (t, 4H), 3.57 (s, 2H), 3.33 (d, 2H), 3.18 (s,4H), 2.94 (t, 4H), 2.88-2.50 (m, 6H), 2.56 (s, 6H), 2.15-1.90 (m, 2H).

EXAMPLE 133A

2-propanethiol (797 mg) in 1-methyl-2-pyrrolidinone (20 mL) at 25° C.was treated with 60% sodium hydride (419 mg) and 2-fluorobenzaldhyde (1g), stirred for 10 minutes, treated with 1M NaOH (20 mL), and extractedwith diethyl ether. The extract was washed with water and brine anddried (Na₂SO₄), filtered, and concentrated.

EXAMPLE 133B

This example was prepared by substituting EXAMPLE 133A for EXAMPLE 130Cin EXAMPLE 130D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.30 (d, 1H),7.78 (dd, 1H), 7.74 (d, 2H), 7.44 (dt, 2H), 7.33 (d, 2H), 7.28-7.22 (m,4H), 7.17 (tt, 1H), 6.87 (d, 1H), 6.81 (d, 2H), 4.11-4.00 (m, 1H), 3.61(s, 2H), 3.33 (d, 2H), 3.17 (t, 4H), 2.80-2.50 (m, 6H), 2.44-2.36 (m,1H), 2.39 (s, 6H), 2.10-1.86 (m, 2H), 1.23 (d, 6H).

EXAMPLE 134A

A mixture of 3-(R)-((carbobenzyloxy)amino)-γ-butyrolactone, preparedaccording to the procedure described in J. Am. Chem. Soc. 1986, 108,4943-4952, (15 g) and N-methylisopropylamine (25 mL) in diglyme (200 mL)at 120° C. was stirred for 48 hours, and concentrated. The concentratewas flash chromatographed on silica gel with 5% methanol/ethyl acetate.

EXAMPLE 134B

This example was prepared by substituting EXAMPLE 134A for EXAMPLE 18Ain EXAMPLE 18B.

EXAMPLE 134C

This example was prepared by substituting EXAMPLE 134B for EXAMPLE 18Bin EXAMPLE 18C.

EXAMPLE 134D

This example was prepared by substituting EXAMPLE 134C for EXAMPLE 19Cin EXAMPLE 19D.

EXAMPLE 134E

This example was prepared by substituting EXAMPLE 134D for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 134F

This example was prepared by substituting EXAMPLE 8550516E and EXAMPLE837538C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO02/24636, and EXAMPLE 10, respectively, inEXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (d, 1H), 8.16 (s, 1H), 7.79(d, 1H), 7.70 (d, 2H), 7.39-7.28 (m, 4H), 7.25 (td, 2H), 7.18 (dt, 1H),7.12 (dt, 2H), 6.90 (d, 1H), 6.76 (d, 2H), 4.13-4.01 (m, 1H), 3.34 (d,2H), 3.12 (s, 4H), 2.76 (s, 2H), 2.67-2.49 (m, 2H), 2.27 (s, 4H),2.23-2.00 (m, 8H), 1.66 (s, 4H), 1.22-0.96 (m, 8H).

EXAMPLE 135A

This example was prepared by substituting di-n-propylamine forN-methylisopropylamine in EXAMPLE 134A.

EXAMPLE 135B

This example was prepared by substituting EXAMPLE 135A for EXAMPLE 18Ain EXAMPLE 18B.

EXAMPLE 135C

This example was prepared by substituting EXAMPLE 135B for EXAMPLE 18Bin EXAMPLE 18C.

EXAMPLE 135D

This example was prepared by substituting EXAMPLE 135C for EXAMPLE 19Cin EXAMPLE 19D.

EXAMPLE 135E

This example was prepared by substituting EXAMPLE 135D for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 135F

This example was prepared by substituting EXAMPLE 135E and EXAMPLE837538C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO02/24636, and EXAMPLE 1C, respectively, inEXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.44 (d, 1H), 8.18 (s, 1H), 7.78(d, 1H), 7.71 (d, 2H), 7.38-7.29 (m, 4H), 7.24 (tt, 2H), 7.18 (dt, 1H),7.12 (d, 2H), 6.93-6.84 (m, 1H), 6.77 (d, 2H), 4.12-3.98 (m, 1H), 3.32(d, 2H), 3.12 (s, 4H), 2.76 (s, 2H), 2.50-2.30 (m, 2H), 2.27 (s, 4H),2.23-2.14 (m, 6H), 2.10-1.94 (m, 2H), 1.66 (s, 4H), 1.60-1.20 (m, 6H),0.80 (s, 6H).

EXAMPLE 136

This example was prepared by substituting EXAMPLE 135E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.18 (s, 1H),7.89 (d, 1H), 7.72 (d, 2H), 7.51 (dd, 1H), 7.48 (s, 4H), 7.40-7.34 (m,2H), 7.32 (dd, 2H), 7.27-7.21, (m, 3H), 7.16 (tt, 1H), 6.94-6.85 (m,1H), 6.79 (d, 2H), 4.12-4.00 (m, 1H), 3.38 (s, 2H), 3.33 (d, 2H), 3.13(t, 4H), 3.00-2.85 (m, 2H), 2.40 (t, 4H), 2.08-1.93 (m, 2H), 1.60-1.20(m, 8H), 0.81 (s, 6H).

EXAMPLE 137A

This example was prepared by substituting diethylamine forN-methylisopropylamine in EXAMPLE 134A.

EXAMPLE 137B

This example was prepared by substituting EXAMPLE 137A for EXAMPLE 18Ain EXAMPLE 18B.

EXAMPLE 137C

This example was prepared by substituting EXAMPLE 137B for EXAMPLE 18Bin EXAMPLE 18C.

EXAMPLE 137D

This example was prepared by substituting EXAMPLE 137C for EXAMPLE 19Cin EXAMPLE 19D.

EXAMPLE 137E

This example was prepared by substituting EXAMPLE 137D for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 137F

This example was prepared by substituting EXAMPLE 137E and EXAMPLE837538C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in W002/24636, and EXAMPLE 1C, respectively, inEXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.44 (d, 1H), 8.18 (d, 1H), 7.81(dd, 1H), 7.71 (d, 2H), 7.37 (d, 2H), 7.31 (dd, 2H), 7.24 (tt, 2H), 7.18(dt, 1H), 7.12 (d, 2H), 6.92 (d, 1H), 6.77 (d, 2H), 4.17-4.04 (m, 1H),3.34 (d, 2H), 3.12 (s, 4H), 2.95 (m, 6H), 2.76 (s, 2H), 2.27 (s, 4H),2.19 (m, 4H), 2.06 (m, 2H), 1.66 (s, 4H), 1.08 (t, 6H).

EXAMPLE 138

This example was prepared by substituting EXAMPLE 137E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, 1H), 8.18 (s, 1H),7.82 (dd, 1H), 7.72 (d, 2H), 7.52 (dd, 1H), 7.48 (s, 4H), 7.40-7.35 (m,2H), 7.31 (dd, 2H), 7.27-7.22, (m, 3H), 7.17 (tt, 1H), 6.94 (d, 1H),6.79 (d, 2H), 4.15-4.04 (m, 1H), 3.38 (s, 2H), 3.35 (d, 2H), 3.14 (t,4H), 3.13-2.95 (m, 6H), 2.40 (t, 4H), 2.15-2.00 (m, 2H), 1.10 (s, 6H).

EXAMPLE 139A

This example was made by substituting 3-bromobenzyl bromide for2-bromobenzyl bromide in EXAMPLE 2A.

EXAMPLE 139B

This example was made by substituting EXAMPLE 139A and phenylboronicacid for EXAMPLE 2A and 4-chlorophenylboronic acid, respectively, inEXAMPLE 2B.

EXAMPLE 139C

This example was made by substituting EXAMPLE 139B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 139D

This example was made by substituting EXAMPLE 139C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.12 (br, 1H),9.92 (br, 1H), 8.78 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.81 (m, 4H),7.70 (m, 2H), 7.59 (t, 1H), 7.51 (m, 3H), 7.39 (m, 3H), 7.21 (m, 4H),7.00 (d, 2H), 4.44 (m, 2H), 4.07 (m, 2H), 3.67 (t, 2H), 3.39 (m, 4H),3.28 (t, 2H), 3.18 (m, 2H).

EXAMPLE 140

This example was made by substituting EXAMPLE 139C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.15 (br, 1H), 10.11 (br, 1H),9.46 (br, 1H), 8.55 (d, 1H), 8.30 (d, 1H), 7.89 (d, 1H), 7.82 (m, 4H),7.70 (m, 2H), 7.59 (t, 1H), 7.51 (m, 3H), 7.42 (m, 1H), 7.17 (m, 6H),7.02 (d, 2H), 4.46 (m, 2H), 3.50 (m, 13H), 2.74 (d, 6H), 2.14 (q, 2H).

EXAMPLE 141

This example was made by substituting EXAMPLE 139C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.17 (br, 1H),10.10 (br, 1H), 9.77 (br, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.89 (dd,1H), 7.80 (m, 4H), 7.70 (m, 2H), 7.59 (t, 1H), 7.51 (m, 3H), 7.41 (m,1H), 7.18 (m, 6H), 7.01 (d, 2H), 4.46 (m, 2H), 3.60 (m, 21H), 2.17 (q,2H).

EXAMPLE 142A

3,4-Difluorobenzoic acid (1 g) in THF (6 mL) and methanol (3 mL) at 25°C. was treated with 2M (trimethylsilyl)diazomethane in hexane (4 mL),stirred for 2 hours, and concentrated. The concentrate was flashchromatographed on silica gel with 5% ethyl acetate/hexane.

EXAMPLE 142B

EXAMPLE 142A in acetonitrile (6 mL) at 25° C. was treated with K₂CO₃(0.46 g) and piperazine (250 mg), refluxed for 24 hours, cooled to 25°C., treated with K₂CO₃ (0.40 g) and 2-phenylbenzyl bromide (0.53 mL),stirred for 18 hours, and concentrated. The concentate was partitionedbetween ethyl acetate and brine. The extract was dried (Na₂SO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel with 5% acetone/hexane.

EXAMPLE 142C

This example was made by substituting EXAMPLE 142B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 142D

This example was made by substituting EXAMPLE 142C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 9.79 (br, 1H), 9.47 (br, 1H),8.53 (d, 1H), 8.30 (d, 1H), 7.86 (dd, 1H), 7.69 (m, 3H), 7.43 (m, 8H),7.14 (m, 8H), 3.65 (m, 15H), 2.74 (d, 6H), 2.14 (q, 2H).

EXAMPLE 143

This example was made by substituting EXAMPLE 142C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.28 (br, 1H),9.66 (m, 1H), 8.78 (t, 1H), 8.58 (d, 1H), 7.89 (dd, 1H), 7.74 (br, 1H),7.68 (s, 1H), 7.64 (m, 1H), 7.48 (m, 4H), 7.37 (m, 5H), 7.23 (m, 4H),7.05 (t, 2H), 4.38 (m, 2H), 3.24 (m, 12H).

EXAMPLE 144

This example was made by substituting EXAMPLE 142C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (br, 1H),8.54 (d, 1H), 8.30 (d, 1H), 7.86 (dd, 1H), 7.68 (m, 3H), 7.48 (m, 9H),7.13 (m, 6H), 3.63 (m, 23H), 2.18 (m, 2H).

EXAMPLE 145A

This example was made by substituting 3,4,5-trifluorobenzoic acid for3,4-difluorobenzoic acid in EXAMPLE 142A.

EXAMPLE 145B

This example was made by substituting EXAMPLE 145A for EXAMPLE 142A inEXAMPLE 142B.

EXAMPLE 145C

This example was made by substituting EXAMPLE 145B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 145D

This example was made by substituting EXAMPLE 145C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 9.72 (br, 1H), 9.44 (br, 1H),8.51 (d, 1H), 8.27 (d, 1H), 7.84 (dd, 1H), 7.75 (m, 1H), 7.49 (m, 8H),7.36 (m, 3H), 7.18 (m, 6H), 3.50 (m, 15H), 2.74 (d, 6H), 2.13 (q, 2H).

EXAMPLE 146

This example was made by substituting EXAMPLE 145C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (br, 1H),8.72 (t, 1H), 8.55 (d, 1H), 7.87 (dd, 1H), 7.73 (br, 1H), 7.34 (m, 16H),4.36 (m, 2H), 3.25 (m, 12H).

EXAMPLE 147

This example was made by substituting EXAMPLE 1450 and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (br, 1H),8.51 (d, 1H), 8.27 (d, 1H), 7.86 (dd, 1H), 7.75 (m, 1H), 7.49 (m, 7H),7.35 (m, 3H), 7.25 (m, 2H), 7.16 (m, 4H), 4.40 (m, 2H), 4.16 (m, 2H),3.38 (m, 19H), 2.15 (m, 2H).

EXAMPLE 148A

1-Phenylimidazole (0.44 mL) in THF at 0° C. was treated with 2.5Mbutyllithium in hexane (1.7 mL), stirred for 20 minutes, treated withDMF (0.8 mL), stirred for 1.5 hours, and treated with saturated aqueousNH₄Cl and ethyl acetate. The extract was washed with brine and dried(Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 15% acetone/hexane.

EXAMPLE 148B

A mixture of EXAMPLE 1A and EXAMPLE 148A in 1,2-dichloroethane (2 mL) at25° C. was treated with sodium triacetoxyborohydride (368 mg), stirredfor 1 hour, and treated with dichloromethane and 1M NaOH. The extractwas washed with brine and dried (Na₂SO₄), filtered, and concentrated.The concentrate was flash chromatographed on silica gel with 3-5%methanol/dichloromethane.

EXAMPLE 148C

This example was made by substituting EXAMPLE 148B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 148D

This example was made by substituting EXAMPLE 148C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₅) δ 12.02.(br, 1H),8.78 (t, 1H), 8.59 (d, 1H), 7.90 (dd, 1H), 7.80 (d, 1H), 7.77 (d, 2H),7.60 (m, 6H), 7.35 (m, 2H), 7.21 (m, 4H), 6.95 (d, 2H), 4.10 (m, 2H),3.50 (m, 6H), 3.28 (t, 2H), 2.86 (m, 4H).

EXAMPLE 149

This example was made by substituting EXAMPLE 148C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE. 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (br,1H), 9.74 (br, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.87 (dd, 1H), 7.83 (d,1H), 7.78 (d, 2H), 7.61 (m, 6H), 7.17 (m, 6H), 6.95 (d, 2H), 3.53 (m,23H), 2.19 (m, 2H).

EXAMPLE 150A

This example was made by substituting 1-phenylpyrazole for1-phenylimidazole in EXAMPLE 148A.

EXAMPLE 150B

This example was made by substituting EXAMPLE 150A for EXAMPLE 148A inEXAMPLE 148B.

EXAMPLE 150C

This example was made by substituting EXAMPLE 150B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 150D

This example was made by substituting EXAMPLE 150C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.07 (br, 1H),8.78 (t, 1H), 8.59 (d, 1H), 7.91 (dd, 1H), 7.76 (d, 2H), 7.75 (s, 1H),7.52 (m, 5H), 7.36 (m, 2H), 7.21 (m, 4H), 6.95 (d, 2H), 6.67 (br, 1H),3.28 (t, 2H), 3.22 (m, 12H).

EXAMPLE 151

This example was made by substituting EXAMPLE 150C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (br, 1H),9.76 (br, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.87 (dd, 1H), 7.77 (d, 2H),7.74 (s, 1H), 7.54 (m, 5H), 7.17 (m, 6H), 6.95 (d, 2H), 6.64 (br, 1H),3.25 (m, 23H), 2.17 (m, 2H).

EXAMPLE 152A

3-Phenyl-3H-imidazole-4-carboxylic acid ethyl ester, prepared asdescribed in Tet. Lett. 2000, 41, 5453-5456, (150 mg) in dichloromethane(2.5 mL) at −78° C. was treated with 1M DIBAL in dichloromethane (1.4mL), stirred for 30 minutes, and treated with 25% aqueous potassiumsodium tartrate, ethyl acetate (50 mL) and 25% aqueous potassium sodiumtartrate (50 mL). The extract was washed with 25% aqueous potassiumsodium tartrate (50 mL) and brine (50 mL) and dried (Na₂SO₄), filtered,and concentrated. The concentrate was flash chromatographed on silicagel with 20-30-50% acetone/hexane.

EXAMPLE 152B

This example was made by substituting EXAMPLE 152A for EXAMPLE 148A inEXAMPLE 148B.

EXAMPLE 152C

This example was made by substituting EXAMPLE 152B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 152D

This example was made by substituting EXAMPLE 152C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d, 1H),8.36 (d, 1H), 7.88 (d, 1H), 7.80 (dd, 1H), 7.72 (d, 2H), 7.61 (m, 2H),7.50 (m, 3H), 7.22 (m, 5H), 7.03 (m, 2H), 6.85 (d, 2H), 4.14 (m, 2H),3.38 (m, 8H), 2.40 (m, 9H), 2.00 (m, 2H), 1.87 (m, 2H), 1.29 (m, 2H).

EXAMPLE 153A

A mixture of EXAMPLE 30C (50.5 mg) and 3-azetidinecarboxylic acid (13mg) in methanol (1 mL) at 25° C. were treated with sodiumcyanoborohydride (8.5 mg), stirred for 4 hours, treated with silica geland concentrated. The concentrate was flash chromatographed on silicagel with 5% methanol/dichloromethane, 20% methanol/2% water/0.2% aceticacid/dichloromethane and 40% methanol/10% water/1% aceticacid/dichloromethane.

EXAMPLE 153B

A mixture of EXAMPLE 2C (1 g) and N-hydroxysuccinimide (296 mg) in ethylacetate (9 mL) and THF (4 mL) at 25° C. was treated with1,3-dicyclohexylcarbodiimide (556 mg), stirred at 40° C. for 6 hours andat 25° C. for 16 hours, cooled to 0° C., treated with 40% ethylacetate/hexane, and filtered through silica gel with 40% ethylacetate/hexane. The filtrate was concentrated and the concentrate wasflash chromatographed on silica gel with 35-40% ethyl acetate/hexane.

EXAMPLE 153C

A mixture of EXAMPLE 153A (28 mg) and EXAMPLE 153B (34 mg) in DMF (0.4mL) at 25° C. was treated with DBU (0.031 mL), stirred for 20 hours, andconcentrated. The concentrate was flash chromatographed on silica gelwith 5% methanol/dichloromethane, 10% methanol/1% water/0.1% aceticacid/dichloromethane, and 20% methanol/20% water/2% aceticacid/dichloromethane. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, 1H), 8.30(br, 1H), 7.81 (dd, 1H), 7.72 (d, 2H), 7.46 (m, 5H), 7.26 (m, 7H), 6.93(m, 1H), 6.81 (d, 2H), 4:06 (m, 2H), 2.99 (m, 16H), 1.65 (m, 4H).

EXAMPLE 154A

This example was made by substituting 1,1-dimethylethanolamine forazetidine hydrochloride in EXAMPLE 30D.

EXAMPLE 154B

This example was made by substituting EXAMPLE 154A for EXAMPLE 153A inEXAMPLE 153C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.12 (d, 1H),7.82 (dd, 1H), 7.72 (d, 2H), 7.51 (m, 5H), 7.26 (m, 7H), 6.93 (d, 1H),6.78 (d, 2H), 4.10 (m, 2H), 3.26 (m, 7H), 2.92 (m, 2H), 2.75 (m, 2H),2.40 (m, 4H), 2.08 (m, 2H), 1.14 (s, 6H).

EXAMPLE 155A

This example was made by substituting sarcosine for3-azetidinecarboxylic acid in EXAMPLE 153A.

EXAMPLE 155B

This example was made by substituting EXAMPLE 155A for EXAMPLE 153A inEXAMPLE 153C. ¹H NMR (300 MHz, DMSO-d₆) δ 12.08 (br, 1H), 9.76 (br, 1H),8.52 (d, 1H), 8.28 (d, 1H), 7.85 (dd, 1H), 7.77 (d, 2H), 7.69 (br, 1H),7.43 (m, 7H), 7.15 (m, 6H), 6.93 (d, 2H), 5.56 (br, 1H), 4.21 (m, 2H),4.03 (m, 2H), 3.37 (m, 11H), 2.79 (s, 3H), 2.19 (m, 2H), 1.65 (m, 2H).

EXAMPLE 156A

This example was made by substituting D-proline for3-azetidinecarboxylic acid in EXAMPLE 153A.

EXAMPLE 156B

This example was made by substituting EXAMPLE 156A for EXAMPLE 153A inEXAMPLE 153C. ¹H NMR (300 MHz, DMSO-d₆) δ 12.15 (br, 1H), 9.67 (br, 1H),8.52 (d, 1H), 8.29 (d, 2H), 7.80 (m, 4H), 7.44 (m, 7H), 7.15 (m, 4H),6.93 (d, 2H), 5.56 (br, 1H), 4.30 (m, 3H), 2.33 (m, 21H).

EXAMPLE 157A

This example was made by substituting isonipecotic acid for3-azetidinecarboxylic acid in EXAMPLE 153A.

EXAMPLE 157B

This example was made by substituting EXAMPLE 157A for EXAMPLE 153A inEXAMPLE 153C. ¹H NMR (300 MHz, DMSO-d₆) δ 12.05 (br, 1H), 8.47 (d, 1H),8.21 (m, 1H), 7.81 (dd, 1H), 7.72 (d, 2H), 7.50 (m, 5H), 7.27 (m, 9H),6.97 (m, 1H), 6.82 (d, 2H), 4.10 (m, 2H), 3.35 (m, 10H), 3.17 (m, 3H),2.50 (m, 4H), 2.40 (m, 3H), 2.07 (m, 2H), 1.63 (m, 2H).

EXAMPLE 158A

This example was made by substituting 2-(methylamino)ethanol forazetidine hydrochloride in EXAMPLE 30D.

EXAMPLE 158B

This example was made by substituting EXAMPLE 158A for EXAMPLE 153A inEXAMPLE 153C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.18 (d, 1H),7.81 (dd, 1H), 7.72 (d, 2H), 7.51 (m, 5H), 7.27 (m, 8H), 6.93 (d, 1H),6.79 (d, 2H), 5.10 (m, 1H), 4.09 (m, 2H), 3.61 (m, 4H), 3.39 (m, 2H),3.14 (m, 4H), 2.97 (m, 3H), 2.62 (m, 3H), 2.50 (m, 3H), 2.40 (m, 4H),2.09 (m, 2H).

EXAMPLE 159A

This example was made by substituting L-proline for3-azetidinecarboxylic acid in EXAMPLE 153A.

EXAMPLE 159B

This example was made by substituting EXAMPLE 159A for EXAMPLE 153A inEXAMPLE 153C. ¹H NMR (300 MHz, _(DMSO-d) ₆) δ 12.10 (br, 1H), 9.67 (br,1H), 8.52 (d, 1H), 8.29 (d, 2H), 7.46 (m, 15H), 6.93 (d, 2H), 5.56 (br,1H), 4.24 (m, 3H), 2.35 (m, 21H).

EXAMPLE 160A

A mixture of 3-azetidinecarboxylic acid (251 mg) and 1M NaOH (6 mL) indioxane (6 mL) at 25° C. was treated with 95% benzyl chloroformate (0.54mL), stirred for 18 hours and concentrated. The concentrate was treatedwith water, and the mixture was adjusted to pH greater than 10, washedwith diethyl ether, adjusted to pH less than 3, and extracted withdichloromethane. The extract was dried (Na₂SO₄), filtered, andconcentrated.

EXAMPLE 160B

EXAMPLE 833294A (574 mg) in dichloromethane (5 mL) at 0° C. was treatedwith oxalyl chloride (0.75 mL) and DMF (2 drops), stirred for 1 hour,and concentrated twice from dichloromethane. The concentrate in ethylacetate (5 mL) was treated with 30% aqueous ammonium hydroxide (1.3 mL)while cooling in a bath of cold water, stirred at 25° C. for 2 hours,and treated with water and dichloromethane. The water layer wasextracted with ethyl acetate, and the combined extracts were dried(Na₂SO₄), filtered, and concentrated.

EXAMPLE 160C

EXAMPLE 833294B (481 mg) in DMF (4 mL) at 25° C. was treated withcyanuric chloride (189 mg), stirred for 30 minutes, and treated withwater and ethyl acetate. The extract was washed with 1M NaHCO₃ and waterand dried (Na₂SO₄), filtered, and concentrated. The concentrate wasflash chromatographed on silica gel with 20% acetone/hexane.

EXAMPLE 160D

A mixture of EXAMPLE 160C (394 mg), azidotrimethylsilane (0.52 mL), anddibutyltin oxide (45 mg) in toluene (3.5 mL) at reflux was stirred for38 hours, treated with methanol, and concentrated twice from methanol.The concentrate was treated with ethyl acetate and saturated NaHCO₃. Thewater layer was adjusted to pH less than 2 with 12M HCl and extractedwith ethyl acetate. The extract was dried (MgSO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 2% methanol/dichloromethane and 5% methanol/0.5% aceticacid/dichloromethane.

EXAMPLE 160E

A mixture of EXAMPLE 160D (224 mg) and palladium black (0.20 g) at 25°C. was treated with a mixture of 96% formic acid (0.19 mL) in methanol(4 mL), stirred for 30 minutes, filtered, concentrated, andreconcentrated from methanol.

EXAMPLE 160F

This example was made by substituting EXAMPLE 160E for3-azetidinecarboxylic acid in EXAMPLE 153A.

EXAMPLE 160G

This example was made by substituting EXAMPLE 160F for EXAMPLE 153A inEXAMPLE 153C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, 1H), 8.36 (d, 1H),7.82 (dd, 1H), 7.70 (m, 3H), 7.32 (m, 12H), 6.99 (d, 1H), 6.83 (d, 2H),2.93 (m, 22H).

EXAMPLE 161A

A mixture of EXAMPLE 832729 (25 mg), Boc-Ala-Ala-OH (9 mg), EDAC.HCl (7mg), and HoBT (6 mg) in dichloromethane (0.5 mL) at 25° C. was treatedwith DIEA (0.009 mL), stirred for 16 hours, and treated with water andethyl acetate. The extract was washed with 20% aqueous NH₄Cl and brine(25 mL) and dried (Na₂SO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 8%methanol/dichloromethane.

EXAMPLE 161B

EXAMPLE 161A (15 mg) in dichloromethane (1 mL) at 25° C. was treatedwith water (0.08 mL) and TFA (0.6 mL), stirred for 1 hour, andconcentrated twice from dichloromethane. ¹H NMR (300 MHz, DMSO-d₆) δ12.09 (br, 1H), 9.68 (br, 1H), 8.52 (d, 1H), 8.51 (d, 1H), 8.29 (d, 1H),8.05 (m, 3H), 7.77 (m, 4H), 7.52 (m, 3H), 7.37 (m, 3H), 7.17 (m, 7H),6.93 (d, 2H), 3.55 (m, 17H), 1.92 (m, 2H), 1.30 (d, 3H), 1.18 (d, 3H).

EXAMPLE 162A

This example was made by substituting 5-pyrrolidin-2-yltetrazole,prepared as described in J. Med. Chem. 1985, 28, 1067-1071, for3-azetidinecarboxylic acid in EXAMPLE 153A.

EXAMPLE 162B

This example was made by substituting EXAMPLE 162A for EXAMPLE 153A inEXAMPLE 153C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d, 1H), 8.27 (d, 1H),7.85 (dd, 1H), 7.73 (d, 2H), 7.43 (m, 7H), 7.17 (m, 7H), 6.88 (d, 2H),4.11 (m, 3H), 2.88 (m, 17H), 1.93 (m, 4H).

EXAMPLE 163A

This example was made by substituting isonipecotic acid for3-azetidinecarboxylic acid in EXAMPLE 160A.

EXAMPLE 163B

This example was made by substituting EXAMPLE 163A andmethanesulfonamide for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D.

EXAMPLE 163C

This example was made by substituting EXAMPLE 163B for EXAMPLE 160D inEXAMPLE 160E.

EXAMPLE 163D

This example was made by substituting EXAMPLE 163C for3-azetidinecarboxylic acid in EXAMPLE 153A.

EXAMPLE 163E

This example was made by substituting EXAMPLE 163D for EXAMPLE 153A inEXAMPLE 153C. MS (ESI) m/e 974.1 (M+H).

EXAMPLE 164A

This example was made by substituting EXAMPLE 18C for 19C in EXAMPLE19D.

EXAMPLE 164B

4-Bromobenzenesulfonyl chloride (0.40 g) in dichloromethane (10 mL) at0° C. was treated with TEA (0.26 mL), bis(2,4-dimethoxybenzyl)amine,prepared as described in Synthesis, 1991, 703-708, (0.50 g) and DMAP,(35 mg), stirred at 25° C. for 4.5 hours, and treated with water andethyl acetate. The extract was washed with brine and dried (Na₂SO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel with 20% ethyl acetate/hexane.

EXAMPLE 164C

A mixture of EXAMPLE 164A (356 mg), EXAMPLE 164B (151 mg), sodiumtert-butoxide (91 mg), tris(dibenzylideneacetone)dipalladium(0) (32 mg)and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (42 mg) in toluene(3 mL) at reflux was stirred for 3.5 hours, and treated with ethylacetate and brine. The extract was dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 2-4% methanol/dichloromethane.

EXAMPLE 164D

A mixture of EXAMPLE 164C (0.34 g) and triethylsilane (0.25 mL) indichloromethane (5 mL) at 25° C. was treated with TFA (0.5 mL), stirredfor 1.25 hours, and concentrated twice from dichloromethane. Theconcentrate was flash chromatographed on silica gel with 5%methanol/dichloromethane and 5-10% methanol/NH₃gas-saturated/dichloromethane.

EXAMPLE 164E

This example was made by substituting EXAMPLE 164D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (d, 2H), 7.57 (d, 2H),7.48 (m, 5H), 7.29 (m, 8H), 6.86 (d, 2H), 6.51 (br, 1H), 6.47 (d, 2H).

EXAMPLE 165A

EXAMPLE 163A (0.50 g) in dichloromethane (5 mL) at 0° C. was treatedwith DMF (2 drops) and oxalyl chloride (0.58 mL), stirred for 10minutes, stirred at 25° C. for 30 minutes, and concentrated twice fromdichloromethane. The concentrate in THF (5 mL) at 25° C. was treatedwith 50% aqueous hydroxylamine (0.46 mL), stirred for 17 hours andconcentrated. The concentrate in ethyl acetate was washed with 0.5M HCl,water, and brine, dried (Na₂SO₄), filtered, and concentrated.

EXAMPLE 165B

This example was made by substituting EXAMPLE 165A for EXAMPLE 160D inEXAMPLE 160E.

EXAMPLE 165C

This example was made by substituting EXAMPLE 165B for3-azetidinecarboxylic acid in EXAMPLE 153A.

EXAMPLE 165D

This example was made by substituting EXAMPLE 165C for EXAMPLE 153A inEXAMPLE 153C.

EXAMPLE 166A

This example was made by substituting 4-bromo-2-chlorobenzenesulfonylchloride for 4-bromobenzenesulfonyl chloride in EXAMPLE 164B.

EXAMPLE 166B

This example was made by substituting EXAMPLE 166A for EXAMPLE 164B inEXAMPLE 164C.

EXAMPLE 166C

This example was made by substituting EXAMPLE 166B for EXAMPLE 164C inEXAMPLE 164D.

EXAMPLE 166D

This example was made by substituting EXAMPLE 166C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 7.74 (d, 2H), 7.65 (d, 1H),7.50 (m, 5H), 7.30 (m, 9H), 6.83 (d, 2H), 6.47 (m, 1H), 6.39 (m, 2H),3.59 (m, 1H), 3.39 (s, 2H), 3.17 (m, 4H), 3.08 (m, 2H), 2.73 (m, 2H),2.51 (s, 3H), 2.49 (s, 3H), 2.40 (m, 4H), 2.00 (m, 1H), 1.75 (m, 1H).

EXAMPLE 167A

This example was made by substituting4-bromo-2,6-dichlorobenzenesulfonyl chloride for 4-bromobenzenesulfonylchloride in EXAMPLE 164B.

EXAMPLE 167B

This example was made by substituting EXAMPLE 167A for EXAMPLE 164B inEXAMPLE 164C.

EXAMPLE 167C

This example was made by substituting EXAMPLE 167B for EXAMPLE 164C inEXAMPLE 164D.

EXAMPLE 167D

This example was made by substituting EXAMPLE 167C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. H NMR (300 MHz, DMSO-d₆) δ 7.73 (d, 2H), 7.51 (m, 5H),7.30 (m, 9H), 6.81 (d, 2H), 6.48 (m, 1H), 6.43 (s, 2H), 3.55 (m, 1H),3.39 (s, 2H), 3.17 (m, 4H), 3.07 (m, 2H), 2.87 (m, 2H), 2.51 (s, 3H),2.49 (s, 3H), 2.41 (m, 4H), 2.02 (m, 1H), 1.75 (m, 1H).

EXAMPLE 168A

Tropane in 1,2-dichloroethane (8 mL) at 0° C. was treated with1-chloroethyl chloroformate (0.47 mL), stirred for 15 minutes, refluxedfor 2 hours, and concentrated twice from dichloromethane. Theconcentrate in methanol (8 mL) was refluxed for 2 hours and concentratedtwice from dichloromethane.

EXAMPLE 168B

This example was made by substituting EXAMPLE 168A for azetidinehydrochloride in EXAMPLE 30D.

EXAMPLE 168C

This example was made by substituting EXAMPLE 168B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.87 (m, 1H), 8.44 (d, 1H),8.09 (m, 1H), 7.82 (m, 1H), 7.71 (d, 2H), 7.50 (m, 5H), 7.27 (m, 8H),6.92 (m, 1H), 6.78 (d, 2H), 4.07 (m, 1H), 3.90 (m, 2H), 3.38 (m, 3H),3.12 (m, 4H), 2.97 (m, 2H), 2.41 (m, 4H), 2.09 (m, 4H), 1.83 (m, 4H),1.61 (m, 4H), 1.48 (m, 1H).

EXAMPLE 169A

This example was made by substituting 7-aza-bicyclo[2.2.1]heptanehydrochloride, prepared as described in Org. Lett. 2001,3, 1371-1374,for azetidine hydrochloride in EXAMPLE 30D.

EXAMPLE 169B

This example was made by substituting EXAMPLE 169A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (m, 1H), 8.44 (d, 1H),8.13 (m, 1H), 7.82 (d, 1H), 7.71 (d, 2H), 7.51 (m, 5H), 7.27 (m, 8H),6.92 (d, 1H), 6.78 (d, 2H), 4.12 (m, 3H), 3.38 (m, 3H), 3.13 (m, 4H),2.97 (m, 2H), 2.40 (m, 4H), 2.09 (m, 3H), 1.85 (m, 4H), 1.58 (m, 4H).

EXAMPLE 170A

This example was made by substituting 1-bromo-2-nitrobenze for1-fluoro-2-(trifluoromethyl)benzene in EXAMPLE 18D.

EXAMPLE 170B

This example was made by substituting EXAMPLE 170A for4-bromobenzenesulfonyl chloride in EXAMPLE 164B.

EXAMPLE 170C

EXAMPLE 170B (150 mg) at 25° C. was treated with a mixture of 95% sodiumhydride (8 mg) and 2-(phenylsulfanyl)ethanol (0.042 mL) in DMF (1.5 mL),stirred for 6 hours and treated with ethyl acetate and brine. The waterlayer was extracted with ethyl acetate, and the extract was dried(Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 25% acetone/hexane.

EXAMPLE 170D

This example was made by substituting EXAMPLE 170C for EXAMPLE 164C inEXAMPLE 164D.

EXAMPLE 170E

This example was made by substituting EXAMPLE 170D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (d, 1H), 8.08 (dd, 1H),7.73 (d, 2H), 7.35 (m, 14H), 6.85 (d, 2H), 4.41 (t, 2H), 3.46 (m, 2H),3.39 (t, 2H), 3.23 (m, 4H), 2.44 (m, 4H).

EXAMPLE 171A

This example was made by substituting4-bromo-3-trifluoromethylbenzenesulfonyl chloride for4-bromobenzenesulfonyl chloride in EXAMPLE 164B.

EXAMPLE 171B

This example was made by substituting EXAMPLE 171A for EXAMPLE 170B inEXAMPLE 170C.

EXAMPLE 171C

This example was made by substituting EXAMPLE 171B for EXAMPLE 164C inEXAMPLE 164D.

EXAMPLE 171D

This example was made by substituting EXAMPLE 171C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (m, 2H), 7.71 (d, 2H),7.50 (m, 5H), 7.30 (m, 9H), 6.84 (d, 2H), 4.36 (t, 2H), 3.41 (s, 2H),3.38 (t, 2H), 3.20 (m, 4H), 2.41 (m, 4H).

EXAMPLE 172A

2(S)-Hydroxymethyl-4(R)-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylicacid tert-butyl ester, prepared as described in J. Med. Chem. 1991,34,2787-2797), (467 mg) in methanol (21 mL) at 25° C. was treated with 95%sodium methoxide (74 mg) in ethanol (3.5 mL), refluxed for 9.5 hours,and concentrated. The concentrate in water and diethyl ether was washedwith brine and dried (MgSO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 20%acetone/hexane.

EXAMPLE 172B

EXAMPLE 172A (178 mg) was treated with 1M HCL in methanol (20 mL),stirred for 21 hours, concentrated, and reconcentrated from diethylether.

EXAMPLE 172C

This example was made by substituting EXAMPLE 172B for azetidinehydrochloride in EXAMPLE 30D.

EXAMPLE 172D

This example was made by substituting EXAMPLE 172C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, 1H), 8.33 (m, 1H),7.79 (dd, 1H), 7.71 (d, 2H), 7.50 (m, 5H), 7.27 (m, 9H), 6.92 (d, 1H),6.80 (d, 2H), 4.43 (m, 1H), 4.09 (m, 1H), 3.85 (m, 1H), 3.54 (m, 1H),3.39 (s, 2H), 3.33 (m, 2H), 3.15 (m, 5H), 2.94 (m, 2H), 2.40 (m, 5H),1.94 (m, 4H), 1.72 (m, 1H).

EXAMPLE 173A

This example was made by substituting2(R)-hydroxymethyl-4(S)-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylicacid tert-butyl ester, prepared as described in J. Med. Chem. 1991,34,2787-2797, for2(S)-hydroxymethyl-4(R)-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylicacid tert-butyl ester in EXAMPLE 172A.

EXAMPLE 173B

This example was made by substituting EXAMPLE 173A for EXAMPLE 172A inEXAMPLE 172B.

EXAMPLE 173C

This example was made by substituting EXAMPLE 173B for azetidinehydrochloride in EXAMPLE 30D.

EXAMPLE 173D

This example was made by substituting EXAMPLE 173C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, 1H), 8.25 (m, 1H),7.81 (dd, 1H), 7.71 (d, 2H), 7.51 (m, 5H), 7.27 (m, 9H), 6.94 (d, 1H),6.80 (d, 2H), 4.46 (m, 1H), 4.14 (m, 1H), 3.87 (m, 1H), 3.56 (m, 1H),3.39 (s, 2H), 3.33 (m, 2H), 3.16 (m, 5H), 2.95 (m, 2H), 2.40 (m, 5H),1.95 (m, 4H), 1.76 (m, 1H).

EXAMPLE 174

This example was made by substituting EXAMPLE 837538C and EXAMPLE 1720for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, 1H),8.32 (m, 1H), 7.81 (dd, 1H), 7.71 (d, 2H), 7.24 (m, 10H), 6.94 (d, 1H),6.79 (d, 2H), 4.45 (m, 1H), 4.11 (m, 1H), 3.87 (m, 1H), 3.56 (m, 1H),3.32 (m, 4H), 3.15 (m, 5H), 2.97 (m, 2H), 2.78 (m, 4H), 2.22 (m, 6H),1.96 (m, 4H), 1.66 (m, 4H).

EXAMPLE 175

This example was made by substituting EXAMPLE 837538C and EXAMPLE 173Cfor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, 1H),8.26 (m, 1H), 7.80 (dd, 1H), 7.71 (d, 2H), 7.24 (m, 10H), 6.94 (d, 1H),6.79 (d, 2H), 4.45 (m, 1H), 4.13 (m, 1H), 3.86 (m, 1H), 3.57 (m, 1H),3.32 (m, 4H), 3.15 (m, 5H), 2.94 (m, 2H), 2.78 (m, 4H), 2.22 (m, 6H),1.95 (m, 4H), 1.66 (m, 4H).

EXAMPLE 176

This example was made by substituting EXAMPLE 837538C and EXAMPLE 169Afor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (br, 1H),8.44 (d, 1H), 8.14 (m, 1H), 7.80 (d, 1H), 7.71 (d, 2H), 7.24 (m, 9H),6.93 (d, 1H), 6.78 (d, 2H), 4.09 (m, 2H), 3.35 (m, 4H), 3.14 (m, 6H),2.76 (br s, 4H), 2.22 (m, 7H), 2.04 (m, 2H), 1.84 (m, 4H), 1.66 (m, 6H).

EXAMPLE 177A

This example was made by substituting 2,5-(cis)-dimethylpyrrolidinetoluenesulfonate, prepared as described in A. R. Katritzky et al. J.Org. Chem. 1999,64, 1979-1985) for azetidine hydrochloride in EXAMPLE30D.

EXAMPLE 177B

This example was made by substituting EXAMPLE 837538C and EXAMPLE 177Afor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.57 (br, 1H),8.45 (d, 1H), 8.15 (m, 1H), 7.81 (d, 1H), 7.71 (d, 2H), 7.24 (m, 9H),6.96 (m, 1H), 6.78 (d, 2H), 4.11 (m, 1H), 3.49 (m, 1H), 3.31 (m, 2H),3.13 (m, 8H), 2.77 (m, 4H), 2.17 (m, 7H), 1.62 (m 6H), 1.29 (m, 6H).

EXAMPLE 178A

A mixture of 2(5H)-furanone (1 mL) and

N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4.2 mL) indichloromethane (30 mL) at 0° C. was treated with TFA (0.10 mL), stirredfor 2.5 hours, and treated with dichloromethane and saturated aqueousNaHCO₃. The extract was washed with brine and dried (Na₂SO₄), filtered,and concentrated. The concentrate was flash chromatographed on silicagel with 15% acetone/hexane.

EXAMPLE 178B

EXAMPLE 178A (2.76 g) in 1,2-dichloroethane (25 mL) at 25° C. wastreated with 95% benzyl chloroformate (3.8 mL), refluxed for 24 hoursand concentrated. The concentrate was flash chromatographed on silicagel with 25% acetone/hexane.

EXAMPLE 178C

EXAMPLE 178B (2.26 g) in THF (40 mL) at −78° C. was treated with 1MDIBAL in dichloromethane (20 mL) then methanol (40 mL), filtered at 25°C., and concentrated. The concentrate was flash chromatographed onsilica gel with 30% acetone/hexane.

EXAMPLE 178D

A mixture of EXAMPLE 178C (1.282 g) and triethylsilane (1.17 mL) indichloromethane (25 mL) at 0° C. was treated with BF₃.diethyl etherate(0.68 mL), stirred at 25° C. for 3 hours, and treated with ethyl acetateand saturated aqueous NaHCO₃. The extract was washed with brine anddried (Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 15% acetone/hexane.

EXAMPLE 178E

This example was made by substituting EXAMPLE 178D for EXAMPLE 160D inEXAMPLE 160E.

EXAMPLE 178F

This example was made by substituting EXAMPLE 178E for azetidinehydrochloride in EXAMPLE 30D.

EXAMPLE 178G

This example was made by substituting EXAMPLE 837538C and EXAMPLE 178Ffor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46. (d, 1H),8.23 (m, 1H), 7.77 (d, 1H), 7.71 (d, 2H), 7.24 (m, 10H), 6.96 (d, 1H),6.79 (d, 2H), 4.08 (m, 1H), 3.61 (m, 2H), 2.68 (m, 26H), 1.66 (m, 6H).

EXAMPLE 179A

Cyclohexanol (880 mg) in DMF (2 mL) a 25° C. was treated with 60% oilyNaH (400 mg) and DMF (3 mL), stirred for 1.5 hours, treated with15-crown-5 (0.6 mL), 4-fluoro-3-nitrobenzenesulfonamide, prepared asdescribed in WO02/24636, (440 mg), and DMF (0.5 mL), stirred for 1.5hours, and treated with water and ethyl acetate. The extract was dried(MgSO₄), filtered, and concentrated. The concentrate was flashchromatagraphed on silica gel with hexanes/ethyl acetate (10-30%).

EXAMPLE 179B

This example was made by substituting EXAMPLE 179A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.31 (d, 1H), 8.07 (dd, 1H),7.72 (d, 2H), 7.55 (t, 2H), 7.40 (m, 7H), 7.23 (dd, 1H), 6.85 (d, 2H),6.73 (m, 1H), 3.51 (s, 2H), 3.23 (s, 4H), 2.44 (s, 4H), 1.85 (m, 2H),1.66 (m, 2H), 1.55 (m, 2H), 1.46 (m, 1H), 1.28 (m, 3H).

EXAMPLE 180A

This example was made by substituting cyclohexylmethanol forcyclohexanol in EXAMPLE 179A.

EXAMPLE 180B

This example was made by substituting EXAMPLE 779855A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (d, 1H), 8.17 (dd, 1H),7.77 (s, 1H), 7.74 (s, 2H), 7.58 (d, 1H), 7.53 (m, 2H), 7.46 (m, 3H),7.37 (m, 3H), 6.93 (d, 2H), 4.31 (br s, 1H), 3.80 (br s, 4H), 3.19 (brs, 3H), 2.83 (br s, 2H), 1.74 (m, 6H), 1.23 (m, 3H), 1.07 (m, 2H).

EXAMPLE 181A

This example was made by substituting 2-cyclohexylethanol forcyclohexanol in EXAMPLE 179A.

EXAMPLE 181B

This example was made by substituting EXAMPLE 181A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.41 (d, 1H), 8.17 (dd, 1H),7.77 (s, 1H), 7.75 (s, 2H), 7.60 (d, 1H), 7.53 (m, 2H), 7.52 (t, 2H),7.43 (t, 1H), 7.37 (m, 3H), 6.92 (d, 2H), 4.30 (t, 4H), 2.95 (br s, 4H),1.71 (d, 2H), 1.65 (m, 8H), 1.46 (m, 1H), 1.18 (m, 4H), 0.94 (m, 2H).

EXAMPLE 182A

Ammonium formate (5.8 g) in water (2.9 mL) at 25° C. was treated withtetrahydropyran-4-one (1 g) in methanol (26 mL), stirred for 5 minutes,treated with 10% Pd/C (1.2 g), stirred for 18 hours, filtered throughdiatomaceous earth (Celite®), and concentrated. A mixture of theconcentrate in ethanol (23 mL) was stirred at 0° C. as 12M HCl (1.7 mL)was added dropwise, stirred for 1 hour, and filtered.

EXAMPLE 182B

This example was made by substituting EXAMPLE 182A for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 182C

This example was made by substituting EXAMPLE 780431B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, 1H), 8.27 (d, 1H),7.93 (dd, 1H), 7.49 (d, 2H), 7.46 (d, 2H), 7.42 (d, 1H), 7.36 (m, 4H),6.90 (d, 2H), 4.22 (br s, 1H), 3.93 (m, 1H), 3.86 (d, 2H), 3.72 (br s,2H), 3.46 (t, 3H), 2.91 (br s, 4H), 2.49 (s, 2H), 1.91 (d, 2H), 1.62 (m,2H).

EXAMPLE 183A

This example was made by substituting 2-cyclohexylethylamine for EXAMPLE21C in EXAMPLE 21D.

EXAMPLE 183B

This example was made by substituting EXAMPLE 183A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.20 (br s, 1H), 8.62 (d,1H), 8.52 (t, 1H), 7.94 (dd, 1H), 7.75 (d, 3H), 7.52 (m, 2H), 7.47 (d,1H), 7.42 (m, 1H), 7.37 (m, 3H), 7.21 (d, 1H), 6.92 (d, 2H), 4.28 (br s,2H), 3.75 (br s, 4H), 3.44 (m, 2H), 3.17 (br s, 2H), 2.86 (br s, 2H),1.73 (d, 2H), 1.65 (m, 2H), 1.52 (m, 2H), 1.36 (m, 1H), 1.18 (m, 4H),0.95 (m, 2H).

EXAMPLE 184A

This example was made by substituting N-methylcyclohexylamine forEXAMPLE 21C in EXAMPLE 21D.

EXAMPLE 184B

This example was made by substituting EXAMPLE 184A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, 1H), 7.89 (dd, 1H),7.75 (d, 3H), 7.52 (m, 2H), 7.47 (d, 2H), 7.43 (m, 2H), 7.37 (m, 3H),6.92 (d, 2H), 4.27 (br s, 2H), 3.81 (br s, 3H), 3.56 (t, 1H), 3.15 (brs, 3H), 2.84 (br s, 2H), 2.65 (s, 3H), 1.76 (t, 4H), 1.59 (m, 3H), 1.35(m, 2H), 1.15 (m, 1H).

EXAMPLE 185A

This example was made by substituting 3,3-dimethylglutarimide forEXAMPLE 18E in EXAMPLE 18F.

EXAMPLE 185B

This example was made by substituting EXAMPLE 185A for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 185C

This example was made by substituting EXAMPLE 185B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.29 (d, 1H), 7.93 (dd, 1H),7.74 (d, 3H), 7.51 (m, 2H), 7.47 (t, 2H), 7.42 (m, 2H), 7.35 (m, 3H),6.91 (d, 2H), 4.29 (s, 2H), 3.79 (br s, 4H), 3.15 (m, 6H), 2.90 (br s,2H), 1.42 (m, 4H), 0.96 (s, 6H).

EXAMPLE 186A

A mixture of tert-butyl-4-oxo-1-piperidinecarboxylate (2 g) in methanol(50 mL) 0° C. was treated with NaBH₄ (2 g), stirred for 0.5 hours,stirred for 2 hours at 25° C., concentrated, treated with water, andextracted with dichloromethane. The extract was washed with water anddried (MgSO₄), filtered, and concentrated.

EXAMPLE 186B

This example was made by substituting EXAMPLE 186A for cyclohexanol inEXAMPLE 179A.

EXAMPLE 186C

This example was made by substituting EXAMPLE 186B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (d, 1H), 8.03 (dd, 1H),7.72 (d, 2H), 7.54 (m, 1H), 7.49 (m, 1H), 7.42 (m, 3H), 7.36 (m, 3H),7.24 (m, 1H), 6.81 (d, 2H), 4.92 (m, 1H), 3.44 (m, 4H), 3.35 (m, 2H),3.17 (d, 4H), 2.41 (m, 4H), 1.87 (m, 2H), 1.60 (m, 2H), 1.40 (s, 9H).

EXAMPLE 187

This example was made by substituting EXAMPLE 186C for EXAMPLE 21B inEXAMPLE 21C. ¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (br s, 1H), 11.58 (br s,1H), 9.31 (s, 1H), 9.08 (s, 1H), 8.46 (d, 1H), 8.19 (dd, 1H), 8.18 (m,1H), 7.76 (d, 2H), 7.71 (d, 1H), 7.52 (t, 2H), 7.46 (t, 2H), 7.42 (d,1H), 7.35 (d, 3H), 6.92 (d, 2H), 5.11 (m, 1H), 4.35 (s, 2H), 3.84 (m,2H), 3.67 (s, 3H), 3.38 (m, 2H), 3.12 (m, 2H), 2.73 (s, 2H), 2.72 (d,1H), 2.15 (m, 2H), 1.98 (m, 2H).

EXAMPLE 188

A mixture of EXAMPLE 187 (53 mg) and 37% formalin (6.6 μL), in 1:1dichloromethane/methanol (1.5 mL) at 25° C. was treated with 2.47 mmol/gMP-NaCNBH₃ (55 mg) and DIEA (1 drop), stirred for 18 hours, treated with1:1 dichloromethane/methanol (5 mL), and filtered through diatomaceousearth (Celite®). The filtrate was dried (MgSO₄), filtered, concentrated.The concentrate was flash chromatographed on silica gel withdichloromethane/2-5%methanol/0.5-1% NH₄OH. ¹H NMR (500 MHz, DMSO-d₆) δ8.28 (d, 1H), 8.04 (dd, 1H), 7.72 (d, 2H), 7.54 (d, 1H), 7.45 (d, 2H),7.46 (t, 2H), 7.42 (m, 3H), 7.36 (m, 3H), 7.24 (dd, 1H), 6.79 (d, 2H),4.91 (s, 1H), 4.42 (s, 2H), 3.14 (m, 8H), 2.74 (s, 3H), 2.39 (m, 4H),2.10 (s, 2H), 1.96 (s, 2H).

EXAMPLE 189

This example was made by substituting4-((cyclohexylmethyl)amino)-3-nitrobenzenesulfonamide for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (m, 2H), 7.93 (dd, 1H),7.78 (d, 2H), 7.72 (s, 1H), 7.52 (d, 4H), 7.40 (d, 2H), 7.33 (m, 1H),7.24 (d, 1H), 6.92 (d, 2H), 4.22 (br s, 1H), 3.82 (br s, 2H), 3.29 (t,4H), 2.88 (br s, 2H), 1.70 (m, 8H), 1.18 (m, 4H), 0.98 (m, 2H).

EXAMPLE 190A

Cyclohexanecarboxaldehyde (2 g) in methanol (20 mL) at 0° C. was treatedwith n-propylamine (0.77 mL) and NaCNBH₃ (600 mg), stirred at 25° C. for18 hours, treated with water, and extracted with diethyl ether. Theextract was dried (MgSO₄), filtered, and concentrated.

EXAMPLE 190B

This example was made by substituting EXAMPLE 190A for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 190C

This example was made by substituting EXAMPLE 190B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, 1H), 7.89 (t, 1H),7.76 (m, 2H), 7.70 (br s, 1H), 7.51 (m, 4H), 7.45 (d, 1H), 7.39 (m, 2H),7.32 (m, 1H),.6.91 (d, 2H),.3.15 (dd, 2H), 3.07 (d, 2H), 2.05 (s, 2H),1.61 (m, 6H), 1.48 (m, 3H), 1.11 (m, 4H), 0.78 (m, 5H).

EXAMPLE 191A

This example was made by substituting 1-N-Boc-4-cyanopiperidine forEXAMPLE 21B in EXAMPLE 21C.

EXAMPLE 191B

A mixture of EXAMPLE 191A (520 mg), K₂CO₃ (1.7 g), benzylbromide (0.62mL), and acetone (7 mL) at reflux was stirred for 2.5 hours andconcentrated. The concentrate was treated with water and 1M HCl, washedwith hexanes, made basic with 2.5M NaOH, and extracted withdichloromethane. The extract was dried (MgSO₄), filtered, andconcentrated.

EXAMPLE 191C

A mixture of EXAMPLE 191B (420 mg) and Raney nickel (4.5 g) in 20%NH₃/methanol (100 mL) at 25° C. was stirred under H₂ at 60 psi for 16hours, filtered, and concentrated.

EXAMPLE 191D

This example was made by substituting EXAMPLE 191C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 191E

This example was made by substituting EXAMPLE 191D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br s, 1H), 11.50 (brs, 1H), 10.68 (br s, 1H), 8.69 (m, 1H), 8.62 (s, 1H), 8.10 (br s, 1H),7.91 (m, 1H), 7.74 (d, 3H), 7.57 (br s, 2H), 7.46 (m, 7H), 7.33 (m, 4H),7.27 (d, 1H), 6.90 (d, 2H), 4.34 (br, s, 2H), 4.20 (m, 2H), 3.81 (m,2H), 3.26 (m, 7H), 3.15 (s, 2H), 2.79 (m, 5H), 2.49 (s, 1H), 1.87 (m,4H), 1.60 (m, 2H), 1.24 (m, 1H), 0.85 (m, 1H).

EXAMPLE 192A

Cyclohexanemethylamine (2 mL) in THF (8 mL) at 25° C. was treated withacetic formic anhydride, prepared as described in Tet. Lett. 1982, 33,3315, (5.7 g), stirred for 3.5 hours, concentrated, cooled to 0° C.,treated with 1M borane.THF (5.1 mL), stirred at reflux for 2.5 hours,concentrated, cooled to 0° C., treated with methanol (10 mL) andmethanolic HCl (50 mL), stirred at reflux for 1 hour, concentrated,treated with water, and washed with diethyl ether. The water layer wasmade basic with 1M KOH and extracted with dichloromethane. The extractwas dried (MgSO₄), filtered, and concentrated.

EXAMPLE 192B

This example was made by substituting EXAMPLE 192A for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 192C

This example was made by substituting EXAMPLE 192B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.27 (d, 1H), 7.86 (dd, 1H),7.74 (m, 3H), 7.52 (m, 2H), 7.47 (m, 2H), 7.42 (m, 2H), 7.35 (m, 3H),6.91 (d, 2H), 4.29 (br s, 2H), 3.27 (d, 4H), 2.81 (m, 3H), 1.63 (m, 8H),1.13 (m,.4H), 0.86 (m, 2H).

EXAMPLE 193A

This example was made by substituting 4-amino-1-benzylpiperidine forEXAMPLE 21C in EXAMPLE 21D.

EXAMPLE. 193B

This example was made by substituting EXAMPLE 193A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br s, 1H), 8.62 (br s,1H), 8.15 (br s, 1H), 7.95 (d, 1H), 7.73 (d, 4H), 7.50 (m, 10H), 7.41(m, 1H), 7.34 (m, 5H), 6.90 (d, 2H), 4.46 (br s, 1H), 4.34 (br s, 2H),4.23 (br s, 1H), 3.92 (br s, 1H), 3.18 (m, 2H), 3.06 (m, 3H), 2.20 (m,2H), 1.83 (br s, 1H).

EXAMPLE 194A

A mixture of tetrahydrothiopyran-4-one (1 g), hyroxylamine hydrochloride(1.5 g), and TEA (3 mL) in absolute ethanol (5 mL) was stirred at refluxfor 3 hours, cooled to 25° C., treated with water, and extracted withdichloromethane. The extract was dried (MgSO₄), filtered, andconcentrated.

EXAMPLE 194B

EXAMPLE 193A (300 mg) was treated with LiAlH₄ (400 mg) in THF (4mL)/diethyl ether (11 mL), stirred at reflux for 5 hours, and processedas described in Fieser and Fieser, Reagents for Organic Synthesis, Vol1, p.584.

EXAMPLE 194C

This example was made by substituting EXAMPLE 194B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 194D

This example was made by substituting EXAMPLE 194C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (br s, 1H), 8.64 (d,1H), 8.31 (d, 2H), 7.94 (dd, 1H), 7.74 (d, 3H), 7.47 (m, 4H), 7.34 (m,3H), 6.91 (d, 4H), 4.29 (br s, 1H), 3.79 (m, 3H), 2.79 (m, 3H), 2.67 (m,2H), 2.21 (m, 2H), 1.75 (m, 2H).

EXAMPLE 195A

This example was made by substituting ethyl4-amino-1-piperidinecarboxylate for EXAMPLE 21C in EXAMPLE 21D.

EXAMPLE 195B

This example was made by substituting EXAMPLE 195A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 8.64 (d,1H), 8.29 (d, 1H), 7.95 (dd, 1H), 7.75 (d, 3H), 7.54 (m, 2H), 7.48 (m,1H), 7.43 (m, 1H), 7.37 (m, 2H), 6.92 (d, 2H), 4.36 (br s, 2H), 4.05 (m,2H), 3.94 (m, 3H), 3.77 (br s, 3H), 3.01 (br s, 4H), 2.83 (br s, 2H),1.94 (d, 2H), 1.55 (m, 2H), 1.19 (t, 5H).

EXAMPLE 196A

This example was made by substituting 1-bromopropane for benzyl bromidein EXAMPLE 191B.

EXAMPLE 196B

This example was made by substituting EXAMPLE 196A for EXAMPLE 191B inEXAMPLE 797197C.

EXAMPLE 196C

This example was made by substituting EXAMPLE 196B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 196D

This example was made by substituting EXAMPLE 196C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, 1H), 8.43 (t, 2H),7.90 (dd, 1H), 7.72 (d, 2H), 7.53 (m, 1H), 7.42 (m, 4H), 7.35 (m, 3H),7.24 (m, 1H), 7.10 (d, 1H), 6.78 (d, 2H), 3.41 (s, 2H), 3.36 (m, 5H),3.13 (m, 4H), 2.77 (m, 3H), 2.39 (m, 4H), 1.87 (d, 3H), 1.59 (m, 2H),1.42 (m, 2H), 0.87 (t, 3H).

EXAMPLE 197A

This example was made by substituting isopropylamine for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 197B

This example was made by substituting EXAMPLE 197A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (d, 1H), 8.24 (d, 1H),7.95 (dd, 1H), 7.74 (m, 3H), 7.50 (m, 4H), 7.42 (m, 1H), 7.35 (m, 3H),7.27 (d, 1H), 6.91 (d, 2H), 4.25 (br s, 2H), 4.00 (m, 1H), 1.28 (d, 6H).

EXAMPLE 198A

A mixture of tributylphosphine (0.8 mL),(1,1′-azodicarbonyl)dipiperidine (0.8 g), and THF (5.1 mL) at 25° C. wasstirred for 10 minutes, treated with tert-butylN-(2-hydroxyethyl)carbamate (0.32 mL), 2-mercaptothiazole (500 mg), andTHF (5 mL), stirred for 20 hours, treated with ethyl acetate (50 mL),washed with water, dried (MgSO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 5-30% ethylacetate/hexanes.

EXAMPLE 198B

This example was made by substituting EXAMPLE 198A for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 198C

This example was made by substituting EXAMPLE 198B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 198D

This example was made by substituting EXAMPLE 198C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (t, 1H), 8.61 (d, 1H),7.96 (dd, 1H), 7.73 (m, 4H), 7.62 (d, 1H), 7.51 (m, 2H), 7.46 (d, 2H),7.40 (m, 2H), 7.34 (m, 4H), 6.91 (d, 2H), 4.28 (br s, 2H), 3.81 (m, 4H),3.50 (t, 4H), 2.06 (s, 2H).

EXAMPLE 199A

This example was made by substituting 4-phenyl-2-mercaptothiazole for2-mercaptothiazole in EXAMPLE 198A.

EXAMPLE 199B

This example was made by substituting EXAMPLE 199A for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 199C

This example was made by substituting EXAMPLE 199B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 199D

This example was made by substituting EXAMPLE 199C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (m, 1H), 8.57 (d, 1H),8.00 (s, 1H), 7.91 (m, 3H), 7.73 (d, 2H), 7.54 (m, 1H), 7.39 (m, 11H),7.24 (m, 1H), 6.86 (d, 2H), 3.87 (m, 2H), 3.57 (dd, 2H), 3.43 (s, 2H),3.22 (m, 4H), 2.39 (m, 4H).

EXAMPLE 200A

This example was made by substituting 2-mercaptobenzthiazole for2-mercaptothiazole in EXAMPLE 198A.

EXAMPLE 200B

This example was made by substituting EXAMPLE 200A for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 200C

This example was made by substituting EXAMPLE 200B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 200D

This example was made by substituting EXAMPLE 200C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.86 (t, 1H), 8.59 (d, 1H),7.76 (m, 4H), 7.54 (m, 2H), 7.48 (m, 2H), 7.43 (m, 2H), 7.36 (m, 4H),6.92 (d, 2H), 4.31 (br s, 2H), 3.91 (m, 2H), 3.66 (t, 4H), 2.97 (br s,4H).

EXAMPLE 201

This example was made by substituting EXAMPLE 198C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (m, 1H), 8.61 (d, 1H),7.95 (dd, 1H), 7.74 (m, 4H), 7.71 (d, 1H), 7.62 (d, 1H), 7.52 (m, 4H),7.40 (m, 1H), 7.39 (m, 2H), 7.37 (m, 1H), 7.33 (m, 1H), 6.91 (d, 2H),3.81 (m, 4H), 3.50 (m, 4H), 3.32 (m, 1H), 3.27 (m, 1H), 2.49 (m, 1H),2.06 (s, 1H).

EXAMPLE 202A

This example was made by substituting 2-mercaptobenzoxazole for2-mercaptothiazole in EXAMPLE 198A.

EXAMPLE 202B

This example was made by substituting EXAMPLE 202A for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 202C

This example was made by substituting EXAMPLE 202B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 202D

This example was made by substituting EXAMPLE 202C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (m, 1H), 8.58 (d, 1H),8.00 (dd, 1H), 7.76 (d, 2H), 7.71 (br s, 1H), 7.57 (m, 2H), 7.50 (m,4H), 7.39 (m, 2H), 7.29 (m, 3H), 6.91 (d, 2H), 4.22 (br s, 2H), 3.92 (m,2H), 3.60 (t, 4H), 2.97 (m, 4H).

EXAMPLE 203

This example was made by substituting EXAMPLE 200C for4-M1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.06 (br s, 1H), 8.85 (t,1H), 8.58 (d, 1H), 8.01 (dd, 1H), 7.97 (d, 1H), 7.75 (m, 3H), 7.71 (brs, 1H), 7.51 (m, 4H), 7.37 (m, 4H), 6.91 (d, 2H), 4.26 (br s, 2H), 3.90(m, 2H), 3.64 (t, 4H), 2.96 (m, 6H).

EXAMPLE 204A

This example was made by substituting 2-mercaptopyrimidine for2-mercaptothiazole in EXAMPLE 198A.

EXAMPLE 204B

This example was made by substituting EXAMPLE 204A for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 204C

This example was made by substituting EXAMPLE 204B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 204D

This example was made by substituting EXAMPLE 204C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 8.83 (t,1H), 8.66 (d, 2H), 8.63 (d, 1H), 8.04 (dd, 1H), 7.76 (d, 2H), 7.72 (brs, 1H), 7.52 (m, 5H), 7.40 (d, 2H), 7.33 (m, 1H), 7.24 (t, 1H), 6.92 (d,2H), 4.29 (br s, 2H), 3.78 (m, 4H), 3.39 (t, 4H), 2.85 (br s, 2H).

EXAMPLE 205A

This example was made by substituting 2-bromoethylamine hydrochloridefor EXAMPLE 21C in EXAMPLE 21D.

EXAMPLE 205B

EXAMPLE 205A and 2-mercaptoimidazole were subjected to the proceduredescribed in J. Med. Chem. 1995, 38, 1067.

EXAMPLE 205C

This example was made by substituting EXAMPLE 205B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (t, 1H), 8.63 (d, 1H),7.94 (dd, 1H), 7.76 (d, 3H), 7.53 (m, 4H), 7.40 (d, 2H), 7.34 (m, 1H),7.30 (m, 1H), 6.93 (d, 2H), 4.26 (br s, 2H), 3.72 (m, 4H), 3.42 (t, 4H),2.98 (br s, 4H).

EXAMPLE 206

This example was made by substituting EXAMPLE 191D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (br s, 1H), 11.43 (brs, 1H), 10.67 (br s, 1H), 8.73 (t, 1H), 8.63 (d, 1H), 8.15 (m, 1H), 7.92(dd, 1H), 7.76 (d, 2H), 7.59 (m, 2H), 7.53 (m, 4H), 7.44 (m, 4H), 7.38(d, 2H), 7.33 (m, 1H), 7.28 (d, 1H), 6.93 (d, 2H), 4.34 (br s, 2H), 4.22(d, 2H), 3.89 (d, 2H), 3.37 (m, 4H), 3.31 (d, 2H), 3.25 (d, 2H), 2.84(m, 4H), 1.88 (d, 3H), 1.61 (m, 2H).

EXAMPLE 207

This example was made by substituting EXAMPLE 205A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (br s, 1H), 8.75 (m,1H), 8.65 (d, ¹H), 7.96 (dd, 1H), 7.75 (d, 3H), 7.53 (m, 2H), 7.48 (m,2H), 7.43 (m, 1H), 7.36 (m, 4H), 6.92 (d, 2H), 4.29 (br s, 2H), 3.88 (m,4H), 3.82 (m, 2H), 3.72 (t, 2H), 3.03 (m, 4H).

EXAMPLE 208A

This example was made by substituting 4-methylthiazole-2-thiol for2-mercaptoimidazole in EXAMPLE 205B.

EXAMPLE 208B

This example was made by substituting EXAMPLE 208A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 8.81 (t,1H), 8.63 (d, ¹H), 7.95 (dd, 1H), 7.76 (d, 2H), 7.73 (br s, 1H), 7.52(m, 3H), 7.39 (d, 2H), 7.34 (m, 1H), 6.93 (d, 2H), 4.25 (br s, 2H), 3.82(m, 2H), 3.48 (m, 4H), 3.02 (m, 4H), 2.29 (s, 3H), 2.07 (s, 2H).

EXAMPLE 209A

This example was made by substituting benzylamine for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand 4-methoxycyclohexane carboxylic acid for EXAMPLE 2C in EXAMPLE 2D.

EXAMPLE 209B

This example was made by substituting EXAMPLE 209A for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 209C

EXAMPLE 209B (710 mg) and Pd(OH)₂ (0.28g) in methanol (70 mL) at 50° C.was stirred under H₂ (60 psi) for 22 hours, cooled to 25°, filtered, andconcentrated.

EXAMPLE 209D

This example was made by substituting EXAMPLE 209C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 209E

This example was made by substituting EXAMPLE 209D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, 1H), 8.48 (t, 1H),7.90 (dd, 1H), 7.72 (d, 2H), 7.51 (m, 1H), 7.47 (s, 3H), 7.37 (m, 2H),7.25 (m, 1H), 7.14 (d, 1H), 6.84 (d, 2H), 3.39 (s, 2H), 3.36 (m, 1H),3.27 (m, 4H), 3.19 (m, 5H), 2.40 (t, 4H), 1.80 (m, 2H), 1.69 (m, 1H),1.48 (m, 2H), 1.33 (m, 4H).

EXAMPLE 210A

This example was made by substituting 2-mercaptothiophene for2-mercaptothiazole in EXAMPLE 198A.

EXAMPLE 210B

This example was made by substituting EXAMPLE 210A for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 210C

This example was made by substituting EXAMPLE 210B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 210D

This example was made by substituting EXAMPLE 210C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (t, 1H), 8.62 (d, 1H),7.90 (dd, 1H),7.75 (m, 2H), 7.61 (dd, 1H), 7.54 (m, 2H), 7.49 (m, 2H),7.43 (m, 1H), 7.36 (m, 2H), 7.21 (dd, 1H), 7.13 (d, 1H), 7.02 (dd, 1H),6.92 (d, 2H), 4.36 (br s, 2H), 3.63 (m, 4H), 3.11 (t, 4H), 2.54 (s, 4H).

EXAMPLE 211A

A mixture of Boc-2-amino-2-methylpropanol (633 mg) and2-thienyldisulfide (1 g) in THF (12 mL) at 25° C. was treated withtributylphosphine (1.1 mL), heated at 85° C. for 2.5 hours, treated withethyl acetate, washed with water, dried (MgSO₄), filtered, andconcentrated. The concentrate was flash chromatograped on silica gelwith 30-70% ethyl acetate/hexanes.

EXAMPLE 211B

This example was made by substituting EXAMPLE 211A for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 211C

This example was made by substituting EXAMPLE 8030757B for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 211D

This example was made by substituting EXAMPLE 211C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (d, 1H), 8.54 (s, 1H),7.82 (dd, 1H), 7.79 (d, 2H), 7.72 (br s, 1H), 7.52 (m, 4H), 7.33 (d,2H), 7.21 (dd, 1H), 6.96 (dd, 1H), 6.94 (d, 2H), 6.66 (dd, 1H), 4.19 (brs, 4H), 2.90 (br s, 6H), 1.54 (s, 6H).

EXAMPLE 212A

This example was made by substituting EXAMPLE 19A forBoc-2-amino-2-methylpropanol and EXAMPLE 22A for 2-thienyldisulfide inEXAMPLE 211A.

EXAMPLE 212B

This example was made by substituting EXAMPLE 212A for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 212C

This example was made by substituting EXAMPLE 212B for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 212D

This example was made by substituting EXAMPLE 212C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 212E

This example was made by substituting EXAMPLE 212D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.97 (br s, 1H), 8.61 (d,1H), 8.34 (d, 1H), 7.95 (dd, 1H), 7.75 (d, 2H), 7.72 (br s, 1H), 7.66(d, 1H), 7.59 (d, 1H), 7.51 (d, 4H), 7.32 (m, 1H), 6.92 (d, 2H), 4.35(m, 2H), 4.22 (br s, 2H), 3.95 (br s, 4H), 3.21 (m, 4H), 2.94 (m, 6H),2.20 (m, 2H).

EXAMPLE 213A

This example was prepared by substituting 2-mercaptopyrimidine for2-mercaptothiazole in EXAMPLE 22A.

EXAMPLE 213B

This example was made by substituting EXAMPLE 18A for

Boc-2-amino-2-methylpropanol and EXAMPLE 213A for 2-thienyldisulfide inEXAMPLE 211A.

EXAMPLE 213C

This example was made by substituting EXAMPLE 213B for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 213D

This example was made by substituting EXAMPLE 213C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 213E

This example was made by substituting EXAMPLE 212D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.08 (br s, 1H), 9.86 (br s,1H), 8.97 (d, 1H) 8.62 (d, 2H,) 8.60 (d, 1H), 7.99 (dd, 1H), 7.77 (d,2H), 7.74 (br s, 1H), 7.53 (m, 5H), 7.39 (d, 2H), 7.34 (m, 1H), 7.22 (t,1H), 6.93 (d, 2H), 4.59 (m, 1H), 4.29 (br s, 2H), 3.42 (dd, 3H), 3.04(dd, 2H), 2.95 (s, 4H), 2.81 (m, 5H).

EXAMPLE 214A

This example was made by substituting EXAMPLE 19A forBoc-2-amino-2-methylpropanol in EXAMPLE 211A.

EXAMPLE 214B

This example was made by substituting EXAMPLE 214A for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 214C

This example was made by substituting EXAMPLE 214B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 214D

This example was made by substituting EXAMPLE 214C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.06 (br s, 1H), 8.77 (d,1H), 7.86 (dd, 1H), 7.74 (d, 2H), 7.71 (br s, 1H), 7.55 (dd, 1H), 7.51(m, 4H), 7.38 (d, 2H), 7.32 (m, 1H), 7.08 (d, 1H), 7.04 (dd, 1H), 6.94(dd, 1H), 6.91 (d, 2H), 4.39 (m, 2H), 3.51 (m, 5H), 3.25 (m, 4H), 2.99(dd, 2H), 2.75 (dd, 2H).

EXAMPLE 215A

This example was made by substituting EXAMPLE 213A for2-thienyldisulfide in EXAMPLE 211A.

EXAMPLE 215B

This example was made by substituting EXAMPLE 215A for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 215C

This example was made by substituting EXAMPLE 215B for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 215D

This example was made by substituting EXAMPLE 215C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, 1H), 8.53 (d, 2H),8.49 (br s, 1H), 7.97 (dd, 1H), 7.74 (d, 2H), 7.53 (m, 2H), 7.47 (br s,4H), 7.37 (m, 2H), 7.25 (m, 1H), 7.11 (t, 1H), 6.87 (d, 2H), 3.80 (br s,2H), 3.41 (br s, 3H), 3.22 (m, 5H), 2.40 (m, 4H), 1.58 (br s, 6H).

EXAMPLE 216C

This example was made by substituting EXAMPLE 22C for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 216D

This example was made by substituting EXAMPLE 216C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.05 (br s, 1H), 8.91 (d,1H), 8.59 (d, 1H), 7.92 (dd, 1H), 7.77 (d, 2H), 7.74 (br s, 1H), 7.71(d, 1H), 7.60 (d, 1H), 7.52 (m, 4H), 7.42 (d, 1H), 7.39 (d, 2H), 7.34(m, 1H), 6.93 (d, 2H), 4.63 (m, 1H), 4.30 (br s, 1H), 3.69 (m, 2H), 3.02(m, 2H), 2.93 (br s, 4H), 2.82 (d, 1H), 2.79 (br s, 4H).

EXAMPLE 217A

This example was made by substituting EXAMPLE 214C for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 217B

This example was made by substituting EXAMPLE 217A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, 1H), 8.38 (m, 1H),7.82 (dd, 1H), 7.72 (d, 2H), 7.58 (dd, 1H), 7.51 (dd, 1H), 7.47 (m, 4H),7.37 (m, 2H), 7.24 (m, 1H), 7.10 (dd, 1H), 6.98 (m, 2H), 6.85 (d, 2H),4.08 (m, 1H), 3.54 (br s, 4H), 3.40 (s, 2H), 3.19 (m, 6H), 2.39 (m,10H), 2.00 (m, 1H), 1.83 (m, 1H).

EXAMPLE 218A

A mixture of EXAMPLE 18A (1.6 g) and 10% Pd/C (0.16 g) in methanol (70mL) at 25° C. was stirred under H₂ (60 psi) for 3 hours, filtered andconcentrated.

EXAMPLE 218B

This example was made by substituting EXAMPLE 218A for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 218C

Methanesulfonyl chloride (68 μL) was treated with EXAMPLE 218B (270 mg)and pyridine (1 mL) at 0° C., stirred for 1 hour, treated with 1M HCl(10 mL) and water, stirred for 0.5 hours, and filtered. The filtrant waswashed with water and concentrated.

EXAMPLE 218D

A mixture of EXAMPLE 218C (120 mg), 4-(trifluoromethoxy)thiophenol (140mg), K₂CO₃ (158 mg), and acetone (14 mL) at reflux was stirred for 30minutes, cooled to 25° C., and concentrated. The concentrate indichloromethane was washed with water and dried (MgSO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 1-2% dichloromethane/methanol.

EXAMPLE 218E

This example was made by substituting EXAMPLE 218D for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 218F

This example was made by substituting EXAMPLE 218D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 9.58 (br s,1H), 8.54 (d, 1H), 8.26 (d, 1H), 7.89 (dd, 1H), 7.77 (d, 2H), 7.72 (brs, 1H), 7.52 (d, 4H), 7.40 (d, 2H), 7.33 (m, 3H), 7.24 (d, 1H), 7.12 (d,2H), 6.92 (d, 2H), 4.23 (m, 2H), 3.43 (m, 4H), 3.13 (m, 4H), 2.74 (br s,6H), 2.14 (m, 2H).

EXAMPLE 219A

This example was made by substituting 2-phenoxyethylamine for EXAMPLE21C in EXAMPLE 21D.

EXAMPLE 219B

This example was made by substituting EXAMPLE 219A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.89 (br s, 1H), 8.71 (t,1H), 8.62 (d, ¹H), 7.97 (dd, 1H), 7.73 (d, 2H), 7.52 (m, 1H), 7.47 (m,4H), 7.37 (m, 3H), 7.26 (m, 3H), 6.94 (m, 3H), 6.88 (d, 2H), 4.24 (t,2H), 3.84 (m, 2H), 3.42 (br s, 2H), 3.24 (m, 4H), 2.41 (m, 4H).

EXAMPLE 220A

This example was made by substituting EXAMPLE 19A for EXAMPLE 18A inEXAMPLE 218A.

EXAMPLE 220B

This example was made by substituting EXAMPLE 220A for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 220C

This example was made by substituting EXAMPLE 220B for EXAMPLE 218B inEXAMPLE 218C.

EXAMPLE 220D

This example was made by substituting EXAMPLE 220C for EXAMPLE 218C inEXAMPLE 218D.

EXAMPLE 220E

This example was made by substituting EXAMPLE 83977F for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 220F

This example was made by substituting EXAMPLE 220E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.70 (br s, 1H), 8.55 (d,1H), 8.26 (d, 1H), 7.90 (dd, 1H), 7.76 (d, 2H), 7.51 (d, 3H), 7.41 (d,2H), 7.33 (m, 3H), 7.24 (d, 1H), 7.13 (d, 2H), 6.92 (d, 2H), 4.23 (m,1H), 3.96 (br s, 2H), 3.61 (br s, 4H), 3.19 (br s, 4H), 3.01 (br s, 2H),2.16 (m, 2H).

EXAMPLE 221A

This example was made by substituting 4-methoxythiophenol for4-(trifluoromethoxy)thiophenol and EXAMPLE 220C for EXAMPLE 218C inEXAMPLE 218D.

EXAMPLE 221B

This example was made by substituting EXAMPLE 221A,for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 221C

This example was made by substituting EXAMPLE 221B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (br s, 1H), 9.86 (br s,1H), 8.56 (d, 1H), 8.25 (d, 1H), 7.87 (dd, 1H), 7.76 (d, 3H), 7.72 (brs, 1H), 7.51 (d, 4H), 7.40 (d, 2H), 7.33 (m, 1H), 7.18 (d, 2H), 7.12 (d,1H), 6.92 (d, 2H), 6.74 (d, 2H), 4.10 (m, 3H), 3.95 (br s, 4H), 3.68 (s,3H), 3.27 (br s, 4H), 3.17 (br s, 4H), 3.01 (br s, 3H), 2.15 (m, 2H).

EXAMPLE 222A

This example was made by substituting 4-methylthiophenol for4-(trifluoromethoxy)thiophenol and EXAMPLE 220C for EXAMPLE 218C inEXAMPLE 218D.

EXAMPLE 222B

This example was made by substituting EXAMPLE 222A for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 222C

This example was made by substituting EXAMPLE 222B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.92 (br s, 1H), 8.53 (d,1H), 8.26 (d, 1H), 7.87 (dd, 1H), 7.78 (d, 2H), 7.74 (m, 1H), 7.53 (m,4H), 7.40 (d, 2H), 7.34 (m, 1H), 7.16 (d, 1H), 7.10 (d, 2H), 6.93 (m,4H), 4.28 (br s, 2H), 4.16 (m, 1H), 3.96 (br s, 2H), 3.62 (br s, 4H),3.34 (d, 2H), 3.18 (m, 4H), 3.01 (br s, 4H), 2.17 (m, 4H).

EXAMPLE 223A

This example was made by substituting EXAMPLE 23C for EXAMPLE 18C inEXAMPLE 18E.

EXAMPLE 223B

This example was made by substituting EXAMPLE 223A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (br s, 1H), 7.98 (d,1H), 7.83 (dd, 1H), 7.73 (m, 3H), 7.63 (dd, 1H), 7.52 (d, 4H), 7.40 (d,2H), 7.33 (m, 1H), 7.13 (m, 1H), 7.03 (m, 1H), 6.92 (d, 2H), 6.80 (d,1H), 6.08 (d, 1H), 4.27 (br s, 4H), 3.85 (m, 2H), 3.17 (m, 4H), 3.06(dd, 2H), 2.99 (m, 2H), 2.10 (m, 2H).

EXAMPLE 224A

This example was made by substituting 4-chlorothiophenol for4-(trifluoromethoxy)thiophenol and EXAMPLE 220C for EXAMPLE 218C inEXAMPLE 218D.

EXAMPLE 224B

This example was made by substituting EXAMPLE 224A for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 224C

This example was made by substituting EXAMPLE 224B for4-(H1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (d, 1H), 8.34 (d, 1H),7.85 (dd, 1H), 7.73 (d, 2H), 7.51 (m, 1H), 7.47 (m, 4H), 7.37 (m, 2H),7.26 (m, 5H), 7.12 (d, 1H), 6.86 (d, 2H), 4.16 (br s, 1H), 3.53 (m, 4H),3.39 (m, 4H), 2.45 (br s, 2H), 2.40 (m, 4H), 1.99 (m, 1H), 1.86 (m, 1H).

EXAMPLE 225A

This example was made by substituting 4-fluorothiophenol for4-(trifluoromethoxy)thiophenol in EXAMPLE 218D.

EXAMPLE 225B

This example was made by substituting EXAMPLE 225A for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 225C

This example was made by substituting EXAMPLE 225B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (d, 1H), 8.04 (d, 1H),7.73 (dd, 1H), 7.61 (d, 2H), 7.39 (m, 1H), 7.36 (br s, 4H), 7.24 (m,4H), 7.13 (dd, 1H), 6.96 (t, 2H), 6.83 (d, 1H), 6.68 (d, 2H), 3.95 (m,1H), 3.27 (br s, 2H), 3.02 (m, 4H), 2.87 (br s, 1H), 2.80 (br s, 1H),2.49 (br s, 6H), 2.28 (m, 4H), 1.94 (m, 2H).

EXAMPLE 226A

This example was made by substituting 4-fluorothiophenol for4-(trifluoromethoxy)thiophenol and EXAMPLE 220C for EXAMPLE 218C inEXAMPLE 218D.

EXAMPLE 226B

This example was made by substituting EXAMPLE 226A for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 226C

This example was made by substituting EXAMPLE 226B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (d, 1H), 8.42 (d, 1H),7.94 (dd, 1H), 7.82 (d, 2H), 7.60 (m, 1H), 7.55 (m, 4H), 7.47 (m, 2H),7.40 (m, 2H), 7.33 (m, 1H), 7.18 (d, 1H), 7.13 (t, 2H), 6.96 (d, 2H),4.22 (br s, 1H), 3.65 (br s, 6H), 3.31 (m, 6H), 2.64 (br s, 4H), 2.54(br s, 2H), 2.49 (m, 4H), 2.09 (m, 1H), 1.97 (m, 1H).

EXAMPLE 227A

This example was made by substituting tert-butyl-1-piperazine forEXAMPLE 1A in EXAMPLE 2A.

EXAMPLE 227B

This example was made by substituting EXAMPLE 227A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 227C

This example was made by substituting EXAMPLE 227B for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 227D

A mixture of ethyl-2,4-difluorobenzoate (194 mg), EXAMPLE 227C (250 mg),and K₂CO₃ (420 mg) in DMSO (1.7 mL) at 125° C. was stirred for 3 hours,cooled to 25° C., treated with dichloromethane, washed with water, anddried (MgSO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 2-10% ethyl acetate/hexanes.

EXAMPLE 227E

This example was made by substituting EXAMPLE 227E for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 227F

This example was made by substituting EXAMPLE 227E for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.92 (br s, 1H), 9.62 (br s,1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.71 (br s, 1H), 7.50(m, 5H), 7.40. (d, 2H), 7.33 (m, 1H), 7.24 (m, 2H), 7.15 (m, 4H), 6.76(m, 2H), 4.21 (m, 2H), 3.40 (d, 3H), 3.15 (m, 4H), 2.75 (br s, 6H), 2.15(m, 2H).

EXAMPLE 228A

A mixture of 1.5M LDA in cyclohexane (5.5 mL) and THF (7.5 mL) at −78°C. was treated with tert-butyl-4-oxo-1-piperidinecarboxylate (1.5 g) inTHF (7.5 mL), stirred for 25 minutes, treated with N-phenylbis(trifluoromethanesulfonamide) (2.8 g) in THF (7.5 mL), stirred for 10minutes, stirred for 3 hours at 0° C., and concentrated. The concentratewas was chromatographed on neutral alumina with 10% ethylacetate/hexanes.

EXAMPLE 228B

A mixture of EXAMPLE 228A (480 mg), 4-ethoxycarbonylphenylboronic acid(308 mg), LiCl (182 mg), tetrakis(triphenylphosphinepalladium (82 mg),and 2M Na₂CO₃ (2 mL) in toluene (4.8 mL) at 90° C. was stirred for 3hours, cooled to 25° C., and treated with water and ethyl acetate.

The extract was washed with water and brine and dried (MgSO₄), filtered,and concentrated. The concentrate was flash chromatographed on silicagel with 2-5% ethyl acetate/hexanes.

EXAMPLE 228C

This example was made by substituting EXAMPLE 228B for EXAMPLE 21B inEXAMPLE 21C.

EXAMPLE 228D

This example was prepared substituting EXAMPLE 228C for EXAMPLE 1A inEXAMPLE 2A.

EXAMPLE 228E

This example was prepared by substituting EXAMPLE 228D for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 228F

This example was prepared by substituting EXAMPLE 228E for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 228G

This example was made by substituting EXAMPLE 228F for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (br s, 1H), 8.30 (d, 1H),8.04 (d, 1H,), 7.63 (m, 3H), 7.53 (m, 1H), 7.30 (m, 2H), 7.24 (d, 2H),7.20 (d, 2H), 7.14 (d, 2H), 7.11 (m, 1H), 6.98 (m, 2H), 6.93 (d, 1H),6.87 (m, 3H), 5.84 (br s, 1H), 4.13 (br s, 2H), 3.94 (m, 1H), 2.89 (m,4H), 2.49 (br s, 6H), 2.24 (m, 2H), 1.89 (m, 2H).

EXAMPLE 229

This example was made by substituting EXAMPLE 228F for EXAMPLE 2C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (br s, 2H), 8.56 (d,1H), 8.30 (d, 1H), 7.89 (d, 3H), 7.79 (m, 1H), 7.55 (m, 2H), 7.50 (m,2H), 7.45 (d, 2H), 7.40 (m, 2H), 7.36 (m, 1H), 7.24 (m, 2H), 7.19 (d,1H), 7.13 (m, 3H), 6.10 (br s, 1H), 4.39 (br s, 2H), 4.20 (m, 1H), 3.95(br s, 3H), 3.40 (m, 4H), 3.18 (m, 4H), 3.02 (br s, 2H), 2.65 (br s,1H), 2.54 (s, 3H), 2.18 (m, 2H).

EXAMPLE 230

This example was prepared by substituting EXAMPLE 227E for EXAMPLE 2Cand EXAMPLE 18F for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (d, 1H), 7.71 (dd, 1H),7.57 (t, 1H), 7.51 (m, 1H), 7.47 (br s, 4H), 7.38 (m, 4H), 7.32 (m, 2H),7.23 (m, 2H), 6.62 (d, 2H), 6.53 (dd, 1H), 3.83 (m, 1H), 3.38 (br s,2H), 3.23 (m, 2H), 3.16 (m, 4H), 2.91 (br s, 1H), 2.74 (br s, 1H), 2.52(br s, 6H), 2.37 (m, 4H), 2.01 (m, 2H).

EXAMPLE 231A

A mixture of methyl-6-chloronicotinate (250 mg), EXAMPLE 227C (458 mg),TEA (0.24 mL), and acetonitrile (1.5 mL) at 95° C. was stirred for 10hours, cooled to 25° C., treated with dichloromethane, washed withwater, and dried (MgSO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 0-2% methanoldichloromethane.

EXAMPLE 231B

This example was made by substituting EXAMPLE 231A for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 231C

This example was made by substituting EXAMPLE 231B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.31 (br s, 1H), 8.36 (d, 1H),8.28 (d, 1H), 8.03 (d, 1H), 7.72 (dd, 1H), 7.61 (dd, 1H), 7.47 (br s,1H), 7.25 (d, 4H), 7.13 (d, 2H), 7.06 (m, 1H), 6.98 (m, 2H), 6.89 (m,4H), 6.60 (d, 1H), 3.94 (m, 4H), 2.88 (m, 4H), 2.49 (br s, 6H), 2.24 (m,2H), 1.89 (m, 2H).

EXAMPLE 232A

This example was made by substituting 1-benzyl-4-piperidone fortert-butyl-4-oxo-1-piperidinecarboxylate in EXAMPLE 228A.

EXAMPLE 232B

This example was made by substituting EXAMPLE 232A for EXAMPLE 228A inEXAMPLE 228B.

EXAMPLE 232C

A mixture of EXAMPLE 232B (0.98 g) and 10% Pd/C (0.1 g) in ethanol (50mL) at 50° C. was stirred under hydrogen for 2 hours, cooled to 25°,filtered, and concentrated.

EXAMPLE 232D

This example was prepared by substituting EXAMPLE 232C for EXAMPLE 1A inEXAMPLE 2A.

EXAMPLE 232E

This example was made by substituting EXAMPLE 232D for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 232F

This example was made by substituting EXAMPLE 232E for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 232G

This example was made by substituting EXAMPLE 232F for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.57 (br s, 1H), 9.46 (br s,1H), 8.55 (d, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.83 (d, 2H), 7.79 (m,1H), 7.55 (m, 4H), 7.40 (d, 2H), 7.35 (m, 1H), 7.28 (d, 2H), 7.23 (d,2H), 7.14 (m, 4H), 4.32 (br s, 2H), 4.19 (m, 2H), 3.39 (d, 2H), 3.29 (d,2H), 3.13 (m, 2H), 2.81 (br s, 2H), 2.74 (br s, 6H), 2.14 (m, 2H), 1.84(m, 3H).

EXAMPLE 233

This example was made by substituting EXAMPLE 232F for EXAMPLE 2C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.98 (m, 1H), 9.51 (br s,1H), 8.55 (d, 1H), 8.30 (d, 1H), 7.87 (dd, 1H), 7.83 (d, 2H), 7.79 (m,1H), 7.56 (m, 4H), 7.40 (d, 2H), 7.35 (m, 1H), 7.28 (d, 2H), 7.24 (d,2H), 7.14 (m, 4H), 4.32 (br s, 2H), 4.19 (m, 1H), 3.93 (br s, 2H), 3.39(d, 4H), 3.29 (d, 3H), 3.18 (br s, 3H), 3.02 (br s, 2H), 2.80 (m, 3H),2.17 (m, 2H), 1.84 (m, 3H).

EXAMPLE 234

This example was prepared by substituting EXAMPLE 228F for EXAMPLE 2Cand EXAMPLE 18F for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.32 (br s, 1H), 7.72 (d,1H), 7.62 (d, 2H), 7.59 (dd, 1H), 7.53 (br s, 1H), 7.29 (m, 2H), 7.25(d, 2H), 7.20 (d, 2H), 7.16 (d, 2H), 7.11 (m, 1H), 7.04 (m, 4H), 6.94(t, 1H), 6.63 (d, 1H), 5.86 (br s, 1H), 5.78 (d, 1H), 4.11 (br s, 1H),3.69 (m, 1H), 2.90 (m, 2H), 2.75 (m, 2H), 2.49 (s, 6H), 2.25 (m, 2H),1.86 (m, 2H).

EXAMPLE 235

This example was made by substituting EXAMPLE 231B for EXAMPLE 2C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.91 (br s, 1H), 8.61 (d,1H), 8.55 (d, 1H), 8.30 (d, 1H), 7.98 (dd, 1H), 7.87 (dd, 1H), 7.74 (brs, 1H), 7.51 (d, 4H), 7.39 (d, 2H), 7.33 (m, 1H), 7.24 (m, 2H), 7.19 (d,1H), 7.13 (m, 3H), 6.86 (d, 1H), 4.33 (br s, 2H), 4.20 (m, 2H), 3.96 (brs, 4H), 3.62 (br s, 4H), 3.40 (m, 4H), 3.19 (m, 3H), 3.01 (br s, 2H),2.80 (br s, 2H), 2.17 (m, 2H).

EXAMPLE 848866

This example was prepared by substituting EXAMPLE 231B for EXAMPLE 2Cand EXAMPLE 18F for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.60 (br s, 1H), 8.60 (d,1H), 7.95 (m, 1H), 7.82 (dd, 1H), 7.73 (br s, 1H), 7.51 (d, 3H), 7.39(d, 2H), 7.30 (m, 4H), 7.19 (m, 1H), 6.88 (d, 1H), 6.85 (d, 1H), 6.04(d, 1H), 3.94 (m, 1H), 3.29 (m, 4H), 3.15 (m, 2H), 3.01 (m, 2H), 2.74(s, 6H), 2.11 (m, 2H).

EXAMPLE 237A

2.5M n-Butyllithium in hexanes (3 mL) at 25° C. was treated withmethyltriphenylphosphonium bromide (2.6 g) in diethyl ether (37 mL),stirred for 1.5 hours, treated with ethyl4-(4-oxopiperidin-1-yl)benzoate, prepared as described in Synthesis1981, 8, 606, (1.47 g), in diethyl ether (15 mL), stirred for 18 hours,and filtered. The filtrate was washed with water and dried (MgSO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel with 10% ethyl acetate/hexanes.

EXAMPLE 237B

A mixture of EXAMPLE 237A (400 mg) and 0.5M 9-BBN (3.3 mL) in THF (2 mL)at 60° C. was stirred for 1.5 hours, cooled to 25° C., treated dropwisewith 2-bromo-4′-chlorobiphenyl (434 mg), K₂CO₃ (296 mg), anddichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II)dichloromethane (24.5 mg) in water (0.36 mL) and DMF (3.6 mL), stirredfor 3 hours at 60° C., cooled to 25° C., and treated with water andethyl acetate. The extract was washed with brine and dried (MgSO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel with 2-5% ethyl acetate/hexanes.

EXAMPLE 237C

This example was made by substituting EXAMPLE 237B for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 237D

This example was made by substituting EXAMPLE 237C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.94 (br s, 1H), 9.43 (br s,1H), 8.54 (d, 1H), 7.87 (dd, 1H), 7.70 (d, 2H), 7.47 (d, 2H), 7.32 (m,3H), 7.27 (dd, 1H), 7.25 (d, 2H), 7.17 (m, 3H), 7.11 (m, 2H), 6.84 (d,2H), 4.20 (m, 1H), 3.78 (d, 2H), 3.39 (d, 2H), 3.14 (m, 2H), 2.74 (s,6H), 2.65 (t, 2H), 2.53 (m, 2H), 2.14 (m, 2H), 1.55 (m, 1H), 1.44 (d,2H), 0.96 (m, 2H).

EXAMPLE 238

This example was made by substituting EXAMPLE 237C for EXAMPLE 2C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.95 (br s, 1H), 9.75 (br s,1H), 8.55 (d, 1H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.70 (d, 2H), 7.48 (m,2H), 7.32 (m, 4H), 7.28 (m, 1H), 7.25 (m, 2H), 7.17 (m, 4H), 7.11 (m,1H), 6.84 (d, 2H), 4.19 (m, 1H), 3.96 (br s, 2H), 3.78 (d, 4H), 3.40 (d,4H), 3.20 (m, 2H), 3.02 (br s, 2H), 2.66 (t, 2H), 2.53 (m, 2H), 2.17 (m,2H), 1.56 (m, 1H), 1.45 (d, 2H), 0.98 (m, 2H).

EXAMPLE 239A

A mixture of, 2,5-dibromopyridine(2.4 g),dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II)dichloromethane (430 mg), and TEA (2.9 mL) in methanol (10 mL), and DMF(10 mL) in a Parr shaker at 50° C. was stirred under CO (200 psi) over5.5 hours, cooled to 25° C., filtered, and concentrated. The concentratewas flash chromatographed on silca gel with 10-20% ethylacetate/hexanes.

EXAMPLE 239B

A mixture of EXAMPLE 239A (900 mg), EXAMPLE 227C (1.6 g), and DIEA (2.1mL) in DMSO (5.9 mL) was stirred at 130° C. for 24 hours, cooled to 25°C., and concentrated. The concentrate was flash chromatagraphed onsilica gel with 30-50% ethyl acetate/hexanes.

EXAMPLE 239C

This example was made by substituting EXAMPLE 239B for EXAMPLE 1B inEXAMPLE 10.

EXAMPLE 239D

This example was made by substituting EXAMPLE 239C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.60 (br s, 1H), 8.59 (d, 1H),8.30 (m, 2H), 7.90 (dd, 1H), 7.82 (d, 1H), 7.70 (br s, 1H), 7.51 (m,4H), 7.41 (d, 2H), 7.38 (dd, 1H), 7.32 (m, 1H), 7.22 (d, 2H), 7.17 (d,1H), 7.12 (m, 3H), 4.19 (m, 2H), 3.39 (d, 2H), 3.13 (m, 4H), 2.74 (s,6H), 2.14 (m, 2H).

EXAMPLE 240

This example was made by substituting EXAMPLE 239C for EXAMPLE 2C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.89 (br s, 1H), 8.59 (d,1H), 8.30 (m, 2H), 7.91 (dd, 1H), 7.83 (d, 1H), 7.73 (br s, 1H), 7.52(d, 4H), 7.40 (m, 3H), 7.34 (m, 1H), 7.23 (d, 2H), 7.18 (d, 1H), 7.12(m, 3H), 4.20 (m, 2H), 3.96 (br s, 4H), 3.40 (d, 2H), 3.19 (m, 2H), 3.01(br s, 4H), 2.17 (m, 2H).

EXAMPLE 241A

EXAMPLE 855947A (12.3 g) inpropan-2-ol (57 mL) at 0° C. was treated withNaBH₄ (2.2 g) in 1:1 ethanol/propane-2-ol (100 mL), stirred at 25° C.for 18 hours, treated with NH₄Cl and brine, and extracted with diethylether. The extract was dried (MgSO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 10-30% ethylacetate/hexanes.

EXAMPLE 241B

This example was made by substituting EXAMPLE 241A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 241C

A mixture of EXAMPLE 241B (420 mg) and TEA (0.95 mL) in dichloromethane(8.7 mL) at 0° C. was treated with methanesulfonyl chloride (0.16 mL),stirred for 0.5 hours, treated with EXAMPLE 228C (0.57 g), stirred for 1hour at 0° C. and for 5 hours at 25° C., treated with dichloromethane,washed with water and brine, and dried (MgSO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 0-2% methanol/dichloromethane.

EXAMPLE 241D

This example was made by substituting EXAMPLE 241C for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 241E

This example was made by substituting EXAMPLE 241D for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, 1H), 8.17 (d, 1H), 7.82(m, 3H), 7.38 (d, 2H), 7.31 (d, 4H), 7.24 (m, 2H), 7.18 (m, 1H), 7.14(m, 2H), 6.90 (d, 1H), 6.13 (br s, 1H), 4.07 (m, 1H), 2.93 (m, 6H), 2.61(m, 6H), 2.39 (br s, 2H), 2.24 (m, 2H), 2.08 (m, 2H), 1.99 (m, 2H), 1.44(t, 2H), 0.97 (br s, 2H).

EXAMPLE 242A

This example was made by substituting2-bromo-cyclohex-1-enecarboxaldehyde, prepared as described in Collect.Czech. Chem. Commun. 1961, 26, 3059-3073, for EXAMPLE 855947A in EXAMPLE241A.

EXAMPLE 242B

This example was made by substituting EXAMPLE 242A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 242C

This example was made by substituting EXAMPLE 242B for EXAMPLE 241B inEXAMPLE 241C.

EXAMPLE 242D

This example was made by substituting EXAMPLE 242C for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 242E

This example was made by substituting EXAMPLE 242D for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 9.69 (br s, 1H), 9.60 (br s,1H), 8.56 (d, 1H), 8.30 (d, 1H), 7.89 (m, 3H), 7.45 (d, 2H), 7.37 (m,2H), 7.17 (m, 8H), 6.14 (br s, 1H), 4.20 (m, 1H), 3.89 (m, 1H), 3.66 (d,4H), 3.40 (d, 3H), 3.12 (m, 4H), 2.75 (br s, 6H), 2.69 (br s, 1H), 2.29(br s, 2H), 2.22 (br s, 2H), 2.15 (m, 2H), 1.71 (br s, 4H).

EXAMPLE 243

This example was made by substituting EXAMPLE 242D for EXAMPLE 2C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (br s, 1H), 9.60 (br s,1H), 8.56 (d, 1H), 8.30 (d, 1H), 7.89 (m, 3H), 7.45 (d, 2H), 7.37 (m,2H), 7.24 (m, 2H), 7.15 (m, 6H), 6.13 (br s, 1H), 4.20 (m, 1H), 3.92 (m,2H), 3.64 (m, 4H), 3.19 (m, 4H), 3.02 (br s, 4H), 2.70 (m, 2H), 2.29 (brs, 2H), 2.18 (m, 4H), 1.71 (br s, 4H).

EXAMPLE 244

This example was made by substituting EXAMPLE 241D for EXAMPLE 2C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, 1H), 8.27 (d, 1H),7.84 (d, 2H), 7.79 (dd, 1H), 7.39 (d, 2H), 7.32 (m, 4H), 7.24 (t, 2H),7.16 (m, 3H), 6.93 (d, 1H), 6.10 (br s, 1H), 4.09 (m, 1H), 3.55 (br s,4H), 3.34 (m, 4H), 3.02 (m, 2H), 2.76 (s, 1H), 2.27 (m, 2H), 2.01 (br s,3H), 1.86 (m, 1H), 1.46 (t, 2H), 0.98 (s, 6H).

EXAMPLE 245A

This example was made by substituting 1,4-cyclohexanedione monoethyleneketal for ethyl 4-(4-oxopiperidin-1-yl)benzoate in EXAMPLE 237A.

EXAMPLE 245B

This example was made by substituting EXAMPLE 245A for EXAMPLE 237A inEXAMPLE 237B.

EXAMPLE 245C

A mixture of EXAMPLE 245B (1.9 g) and 35% aqueous TFA (42 mL) inchloroform (61 mL) was stirred at 25° C. for 7 hours and treated withwater and dichloromethane. The extract was washed with saturated NaHCO₃and brine and dried (MgSO₄), filtered, and concentrated.

EXAMPLE 245D

This example was made by substituting EXAMPLE 245C fortert-butyl-4-oxo-1-piperidinecarboxylate and by substituting2-(N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine forN-phenylbis(trifluoromethanesulfonamide) in EXAMPLE 228A.

EXAMPLE 245E

This example was made by substituting EXAMPLE 245D for EXAMPLE 228A inEXAMPLE 228B.

EXAMPLE 245F

This example was made by substituting EXAMPLE 245E for EXAMPLE 1B inEXAMPLE 10.

EXAMPLE 245G

This example was made by substituting EXAMPLE 245F for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.45 (br s, 1H), 8.56 (d, 1H),8.30 (d, 1H), 7.88 (dd, 1H), 7.81 (d, 2H), 7.47 (d, 2H), 7.42 (d, 2H),7.34 (m, 3H), 7.32 (s, 1H), 7.28 (m, 1H), 7.24 (m, 2H), 7.16 (m, 4H),7.11 (m, 1H), 6.16 (br s, 1H), 4.19 (m, 1H), 3.14 (m, 3H), 2.74 (s, 6H),2.61 (m, 2H), 2.24 (m, 2H), 2.14 (m, 2H), 2.03 (m, 1H), 1.68 (m, 3H),1.17 (m, 1H).

EXAMPLE 246

This example was made by substituting EXAMPLE 245F for EXAMPLE 2C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, 1H), 8.29 (d, 1H),7.87 (dd, 1H), 7.79 (d, 2H), 7.46 (d, 2H), 7.40 (d, 2H), 7.32 (m, 4H),7.27 (m, 1H), 7.23 (m, 2H), 7.15 (m, 4H), 7.10 (m, 1H), 6.14 (br s, 1H),4.18 (m, 1H), 3.77 (br s, 4H), 3.15 (m, 4H), 2.59 (m, 2H), 2.20 (m, 4H),2.02 (d, 1H), 1.67 (m, 3H), 1.15 (m, 1H).

EXAMPLE 247A

This example was made by substituting methyl-4-fluorobenzoate forethyl-2,4-difluorobenzoate and cis-octahydropyrrolo[3,4-c]pyrrole forEXAMPLE 227C in EXAMPLE 227D.

EXAMPLE 247B

This example was made by substituting EXAMPLE 247A for EXAMPLE 1A inEXAMPLE 2A.

EXAMPLE 247C

This example was made by substituting EXAMPLE 247B for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 247D

This example was made by substituting EXAMPLE 247C for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 247E

This example was made by substituting EXAMPLE 247D for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, CDCl₃) δ 8.77 (br s, 1H), 8.34 (d, 1H),7.96 (d, 1H), 7.92 (br s, 1H), 7.65 (brs, 2H), 7.49 (m, 4H), 7.38 (br s,2H), 7.30 (m, 2H), 7.19 (m, 6H), 6.83 (m, 1H), 6.46 (m, 2H), 4.34 (br s,2H), 3.84 (m, 1H), 3.28 (m, 4H), 3.15 (m, 4H), 2.80 (m, 6H), 2.41 (br s,2H).

EXAMPLE 248A

A mixture of 4-chloro-3-nitrobenzenesulfonyl chloride (10 g), TEA (10.87mL), and bis(2,4-dimethoxybenzyl)amine (12.38 g) in dichloromethane (200mL) at 25° C. was stirred for 12 hours, treated with dichloromethane(200 mL), washed with saturated sodium bicarbonate (100 mL) and brine,and concentrated.

EXAMPLE 248B

A mixture of EXAMPLE 248A (20.98 g) and 2M methylamine in THF (400 mL)at 80° C. was stirred for 4 hours and concentrated. The concentrate wastreated with ethyl acetate and saturated sodium bicarbonate. The extractwas dried (Mg₂SO₄), filtered and concentrated.

EXAMPLE 248C

A mixture of EXAMPLE 248B (1 g) and 3.56 mmol/g polymer-supportedN,N-DIEA (2.65 g) in dichloromethane (10 mL) was treated with 20%phosgene in toluene (10.1 mL), heated at 40° C. for 24 hours, filteredand concentrated.

EXAMPLE 248D

A mixture of EXAMPLE 248C (200 mg), TEA (141 μL) andN-methyl-4-trifluoromethoxyphenyl aniline (129 mg) in dichloromethane (2mL) at 50° C. was heated for 12 hours and concentrated. The concentratewas flash chromatographed on silica gel with 70% ethyl acetate/hexane.

EXAMPLE 248E

EXAMPLE 248D (57 mg) in triethylsilane/TFA/dichloromethane (0.05 mL/0.45mL/0.5 mL) was stirred at 25° C. for 30 minutes and concentrated. Theconcentrate was flash chromatographed on silica gel with 80% ethylacetate/hexane.

EXAMPLE 248F

This example was made by substituting EXAMPLE 248E for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (400MHz, DMSO-d₆) δ 8.26 (d, 1H), 7.80 (d, 2H),7.72 (br, 1H), 7.41 (m, 8H), 7.28 (d, 1H), 6.92 (m, 6H), 4.26 (br, 2H),3.74 (br, 2H), 3.13 (br, 2H), 2.96 (s, 6H), 2.82 (br, 2H)

EXAMPLE 249A

This example was made by substituting N-methyl-2-methylanaline forN-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 249B

This example was made by substituting EXAMPLE 249A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 249C

This example was made by substituting EXAMPLE 249B for4-(H1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (400 MHz, DMSO-d₆) 8.30 (d, 1H), 7.86 (d, 1H),7.83 (d, 2H), 7.75 (br, 1H), 7.53 (m, 2H), 7.47 (d, 2H), 7.43 (q, 1H),7.37 (m, 3H), 7.21 (d, 1H), 6.97 (d, 2H), 6.83 (d, 1H), 6.74 (t, 1H),6.64 (t, 1H), 6.56 (d, 1H), 4.31 (br, 2H), 3.80 (br, 2H), 3.18 (s, 3H),3.14 (br, 2H), 2.90 (s, 3H), 2.84 (br, 4H), 1.95 (s, 3H).

EXAMPLE 250A

This example was made by substituting N-methyl-4-methoxyanaline forN-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 250B

This example was made by substituting EXAMPLE 250A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 250C

This example was made by substituting EXAMPLE 250B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, 1H), 7.86 (dd, 1H),7.81 (d, 2H), 7.73 (br, 1H), 7.52 (br, 2H), 7.47 (d, 2H), 7.43 (d, 1H),7.36 (m, 3H), 7.20 (d, 1H), 6.94 (d, 2H), 6.70 (d, 2H), 6.49 (d, 2H),4.28 (br, 2H), 3.81 (br, 2H), 3.43 (s, 3H), 3.19 (s, 3H), 3.14 (br, 2H),2.90 (s, 3H), 2.82 (br, 4H).

EXAMPLE 251A

This example was made by substituting N-methyl-4-methylanaline forN-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 251B

This example was made by substituting EXAMPLE 251A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 251C

This example was made by substituting EXAMPLE 251B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, 1H), 7.83 (m, 3H),7.73 (br, 1H), 7.52 (m, 2H), 7.47 (d, 2H), 7.42 (d, 1H), 7.36 (m, 3H),7.20 (d, 1H), 6.96 (d, 2H), 6.71 (d, 2H), 6.66 (d, 2H), 4.28 (br, 2H),3.80 (br, 2H), 3.22 (s, 3H), 3.14 (br, 2H), 2.91 (s, 3H), 2.82 (br, 4H),1.90 (s, 3H)

EXAMPLE 252A

This example was made by substituting N-diphenylmethyl methylamine forN-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 252B

This example was made by substituting EXAMPLE 252A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 252C

This example was made by substituting EXAMPLE 252B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, 1H), 8.15 (dd, 1H),7.74 (dd, 4H), 7.50 (m, 4H), 7.43 (d, 1H), 7.36 (m, 6H), 7.29 (m, 2H),7.16 (d, 4H), 6.92 (d, 2H), 6.30 (s, 1H), 4.33 (br, 2H), 3.84 (br, 4H),3.25 (s, 3H), 3.13 (br, 3H), 2.82 (br, 2H), 2.69 (s, 3H).

EXAMPLE 253A

This example was made by substituting (S)-(−)-N-methyl-1-phenethylaminefor N-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 253B

This example was made by substituting EXAMPLE 253A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 253C

This example was made by substituting EXAMPLE 253B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, 1H), 8.19 (dd, 1H),7.76 (d, 2H), 7.70 (d, 1H), 7.50 (br, 6H), 7.33 (br, 8H), 6.93 (d, 2H),5.17 (q, 1H), 4.37 (br, 2H) 3.84 (br, 2H), 3.26 (s, 3H), 3.11 (br, 4H),2.84 (br, 2H), 2.61 (s, 3H), 1.46 (d, 3H)

EXAMPLE 254A

This example was made by substituting2-(4-methylpiperazinyl)-1-phenethyl methylamine forN-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 254B

This example was made by substituting EXAMPLE 254A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 254C

This example was made by substituting EXAMPLE 254B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideinEXAMPLE 1D. 1H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, 1H), 8.20 (dd, 1H),7.76 (d, 3H), 7.65 (d, 1H), 7.48 (m, 5H), 7.34 (m, 8H), 6.93 (d, 2H),5.31 (dd, 1H), 4.36 (br, 2H), 3.84 (br, 2H), 3.42 (br, 4H), 3.30 (s,3H), 3.07 (br, 8H), 2.86 (m, 2H), 2.80 (s, 3H), 2.75 (s, 3H), 2.33 (m,2H).

EXAMPLE 255A

This example was made by substituting 2-morpholine-4-yl-1-phenethylmethylamine for N-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 255B

This example was made by substituting EXAMPLE 255A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 255C

This example was made by substituting EXAMPLE 255B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, 1H), 8.15 (dd, 1H),7.76 (m, 3H), 7.66 (d, 1H), 7.47 (m, 13H), 6.93 (d, 2H), 5.57 (br, 1H),4.37 (br, 2H), 3.83 (br, 8H), 3.25 (s, 3H), 3.13 (br, 6H), 2.84 (br,4H), 2.64 (s, 3H)

EXAMPLE 256A

This example was made by substituting (1,2-diphenyl-ethyl)methylaminefor N-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 256B

This example was made by substituting EXAMPLE 256A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 256C

This example was made by substituting EXAMPLE 256B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (400 MHz, DMSO-d₆) δ 8.33 (d, 1H), 8.05 (dd, 1H),7.75 (d, 3H), 7.38 (m, 18H), 7.22 (m, 1H), 6.92 (d, 2H), 5.58 (dd, 1H),4.32 (br, 2H), 3.65 (br, 6H), 3.40 (dd, 1H), 3.22 (dd, 1H), 3.10 (br,2H), 2.69 (s, 3H), 2.66 (s, 3H)

EXAMPLE 257A

This example was made by substituting(2-(methylamino)-2-phenylethyl)dimethylamine forN-methyl-4-trifluoromethoxyaniline in EXAMPLE 248D.

EXAMPLE 257B

This example was made by substituting EXAMPLE 257A for EXAMPLE 248D inEXAMPLE 248E.

EXAMPLE 257C

This example was made by substituting EXAMPLE 257B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. 1H NMR (500 MHz, DMSO-d₆) δ 8.39 (d, 1H), 8.12 (dd, 1H),7.74 (d, 3H), 7.64 (d, 1H), 7.40 (m, 13H), 6.91 (d, 2H), 5.54 (dd, 1H),4.00 (br, 8H), 3.25 (s, 3H), 3.14 (br, 2H), 2.69 (s, 6H), 2.61 (s, 3H)

EXAMPLE 258

A mixture of EXAMPLE 10 (400 mg) and 30% Pd/C (120 mg) in 1:1methanol/ethyl acetate (10 mL) at 25° C. was stirred under H₂ (balloon)for 2 hours and filtered. The filtrate was concentrated and flashchromatographed on silica gel with 40% acetonitrile/dichloromethane. 1HNMR (500 MHz, CDCl₃) δ 7.87 (br, 1H), 7.64 (m, 2H), 7.40 (m, 6H), 7.17(m, 8H), 6.38 (br, 1H), 5.17 (br, 4H), 4.29 (s, 2H), 3.30 (m, 4H), 2.95(s, 2H), 2.49 (br, 2H)

EXAMPLE 259

A mixture of EXAMPLE 258 (50 mg) and sodium nitrite (7.2 mg) inwater/hydrochloric acid/acetic acid (0.38 mL/0.562 mL/2 mL) at 0° C. wasstirred for 2 hours and concentrated. The concentrate in 1:1DMSO/methanol (10.5 mL) and purified by HPLC with 0-70%acetonitrile/water with 0.1% TFA. ¹H NMR (500 MHz, CDCl₃) δ 8.75 (s,1H), 8.23 (dd, 1H), 7.78 (dd, 1H), 7.69 (d, 2H), 7.49 (m, 3H), 7.42 (d,2H), 7.30 (m, 1H), 7.26 (m, 2H), 7.19 (m, 5H), 5.66 (d, 2H), 4.82 (t,2H), 4.39 (s, 2H), 3.50 (t, 2H), 3.42 (br, 8H)

EXAMPLE 260

EXAMPLE 258 (60 mg) in formic acid (2 mL) was heated at 100° C. for 3hours, and concentrated. The concentrate was purified by HPLC with 0-70%acetonitrile/water with 0.1% TFA. 1H NMR (400 MHz, CDCl₃) δ 8.53 (s,1H), 8.46 (s, 1H), 8.13 (d, 1H), 7.75 (dd, 1H), 7.62 (d, 2H), 7.46 (m,4H), 7.30 (dd, 1H), 7.16 (m, 8H), 6.63 (d, 2H), 4.48 (t, 2H), 4.35 (s,2H), 3.42 (br, 4H), 3.35 (t, 2H), 3.00 (br, 4H).

EXAMPLE 261

This example was made by substituting EXAMPLE 90C and4-(cyclohexylmethylamino)-3-nitrobenzenesulfonamide, prepared asdescribed in WO02/24636, for EXAMPLE 1C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 11.95 (m, 1H),8.61 (m, 1H), 7.91 (dd, 1H), 7.67 (d, 2H), 7.44 (m, 1H), 7.39 (m, 1H),7.34 (m, 2H), 7.30 (m, 2H), 7.27 (m, 2H), 7.22 (m, 1H), 7.16 (m, 1H),6.80 (m, 2H), 3.38 (m, 2H), 3.27 (m, 3H), 3.03 (s, 3H), 2.89 (s, 2H),2.84 (m, 1H), 2.76 (m, 1H), 1.77 (m, 1H), 1.66 (m, 5H), 1.47 (m, 2H),1.08 (m, 7H).

EXAMPLE 262

This example was made by substituting EXAMPLE 90C and4-(cyclohexylamino)-3-nitrobenzenesulfonamide, prepared as described inWO02/24636, for EXAMPLE 10 and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (d, 1H),8.31 (d, 1H), 7.92 (dd, 1H), 7.66 (d, 2H), 7.34 (m, 9H), 7.15 (m, 1H),6.79 (d, 2H), 3.71 (m, 1H), 3.39 (d, 2H), 3.02 (m, 3H), 2.84 (m, 4H),1.94 (m, 2H), 1.65 (m, 3H), 1.30 (m, 9H).

EXAMPLE 263

This example was made by substituting EXAMPLE 90C and4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO02/24636, for EXAMPLE 1C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 11.96 (m, 1H),8.51 (m, 2H), 7.82 (dd, 1H), 7.71 (d, 2H), 7.33 (m, 11H), 7.15 (m, 1H),7.00 (m, 2H), 6.92 (m, 1H), 6.82 (d, 2H), 3.54 (s, 2H), 3.40 (m, 2H),3.03 (s, 3H), 2.85 (m, 4H), 1.57 (s, 6H), 1.46 (m, 2H), 1.17 (m, 2H).

EXAMPLE 264A

A mixture of thiophenol (0.2 mL), (1-amino-cyclopentyl)methanol (0.2 g),tributylphosphine (0.5 mL), and THF (30 mL) at 0° C. was treated withADDP (0.482 g), stirred for 1 hour, stirred at 25° C. for 18 hours, andconcentrated. The concentrate was flash chromatographed on silica gelwith 50% ethyl acetate/hexanes and 5% methanol/dichloromethane.

EXAMPLE 264B

This example was prepared by substituting EXAMPLE 264A for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 264C

This example was made by substituting EXAMPLE 264B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.42 (s, 1H),8.35 (d, 1H), 7.74 (m, 4H), 7.39 (m, 8H), 7.11 (m, 3H), 6.79 (m, 5H),4.33 (s, 1H), 3.81 (s, 1H), 3.50 (s, 2H), 3.07 (m, 4H), 2.35 (m, 4H),1.98 (m, 4H), 1.64 (m, 4H).

EXAMPLE 265

This example was made by substituting EXAMPLE 90C and EXAMPLE 264B forEXAMPLE 1C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 11.96 (s, 1H),8.49 (s, 1H), 8.41 (d, 1H), 7.82 (dd, 1H), 7.73 (d, 1H), 7.34 (m, 8H),7.16 (m, 4H), 6.83 (m, 5H), 3.57 (s, 2H), 3.31 (s, 2H), 3.02 (s, 3H),2.85 (m, 4H), 2.11 (m, 2H), 1.99 (m, 2H), 1.71 (m, 4H), 1.47 (m, 2H),1.18 (m, 2H).

EXAMPLE 266

This example was made by substituting EXAMPLE 264B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CD₃OD) δ 8.52 (d, 1H), 7.85 (m, 3H),7.72 (m, 1H), 7.58 (m, 2H), 7.51 (d, 2H), 7.42 (m, 1H), 7.35 (d, 2H),7.12 (m, 2H), 6.99 (m, 3H), 6.72 (m, 3H), 4.46 (s, 2H), 3.50 (s, 2H),3.31 (m, 4H), 3.17 (m, 4H), 2.13 (m, 4H), 1.80 (m, 4H).

EXAMPLE 267A

A mixture of (S)-2-aminobutan-1-ol (1 g), tributylphosphine (3 mL) andphenyl disulfide (2.64 g) in toluene (20 mL) at 85° C. was stirred for16 hours, and concentrated. The concentrate was flash chromatographed onsilica gel with 1% methanol/dichloromethane.

EXAMPLE 267B

This example was prepared by substituting EXAMPLE 267A for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 267C

This example was made by substituting EXAMPLE 267B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CD₃OD) δ 8.30 (d, 1H), 7.90 (dd, 1H),7.75 (d, 2H), 7.52 (m, 1H), 7.38 (m, 6H), 7.24 (m, 3H), 7.05 (m, 2H),6.96 (d, 1H), 6.90 (d, 2H), 3.95 (m, 1H), 3.54 (s, 2H), 3.27 (m, 4H),2.51 (m, 4H), 1.81 (m, 2H), 1.00 (t, 3H).

EXAMPLE 268

This example was made by substituting EXAMPLE 90C and EXAMPLE 267B forEXAMPLE 1C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, 1H),8.37 (m, 1H), 8.01 (d, 1H), 7.57 (m, 2H), 7.35 (m, 10H), 7.19 (m, 4H),6.72 (d, 2H), 6.64 (d, 1H), 3.72 (m, 1H), 3.36 (m, 2H), 3.13 (m, 5H),2.99 (m, 1H), 2.92 (s, 3H), 1.92 (m, 1H), 1.58 (m, 3H), 1.31 (m, 2H),0.98 (t, 3H).

EXAMPLE 269

This example was made by substituting EXAMPLE 267B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.80 (s, 1H), 8.42 (m, 1H),8.03 (dd, 1H), 7.67 (m, 3H), 7.36 (m, 10H), 7.19 (m, 3H), 6.74 (d, 2H),6.65 (d, 1H), 3.64 (m, 3H), 3.31 (m, 4H), 3.11 (s, 2H), 2.53 (m, 4H),1.69 (m, 2H), 0.98 (t, 3H).

EXAMPLE 270A

This example was prepared by substituting(S)-2-amino-4-methyl-pentan-1-ol for (S)-2-Amino-butan-1-ol in EXAMPLE267A.

EXAMPLE 270B

This example was prepared by substituting EXAMPLE 270A for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 270C

This example was made by substituting EXAMPLE 270B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.80 (d, 1H), 8.38 (d, 1H),8.00 (dd, 1H), 7.63 (d, 2H), 7.49 (m, 1H), 7.35 (m, 8H), 7.22 (m, 4H),6.79 (d, 2H), 6.60 (d, 1H), 3.85 (m, 1H), 3.42 (s, 2H), 3.28 (m, 4H),3.09 (d, 2H), 2.47 (m, 4H), 1.73 (m, 3H), 0.96 (d, 3H), 0.86 (d, 3H).

EXAMPLE 271

This example was made by substituting EXAMPLE 90C and EXAMPLE 270B forEXAMPLE 1C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.77 (d, 1H),8.36 (d, 2H), 7.98 (dd, 1H), 7.60 (d, 2H), 7.35 (m, 9H), 7.20 (m, 4H),6.64 (m, 3H), 3.80 (m, 1H), 3.34 (s, 2H), 3.12 (s, 3H), 3.07 (m, 2H),2.92 (m, 4H), 1.57 (m, 5H), 1.30 (m, 2H), 0.95 (d, 3H), 0.85 (d, 3H).

EXAMPLE 272A

1-Tert-butoxycarbonylaminocyclopropane carboxylic acid (1.018 g) in THF(6 mL) at 0° C. was treated with 1M borane·THF (15 mL), stirred at 25°C., treated with 3M NaOH, (5 mL), and extracted with diethyl ether. Theextract was dried (MgSO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 10% ethyl acetate/hexanes.

EXAMPLE 272B

This example was prepared by substituting EXAMPLE 272A for(S)-2-amino-butan-1-ol in EXAMPLE 267A.

EXAMPLE 272C

272B (0.090.g) in dichloromethane/TFA at 25° C. was stirred for 16 hoursand concentrated. The concentrate was flash chromatographed on silicagel with 5% methanol/dichloromethane.

EXAMPLE 272 D

This example was prepared by substituting EXAMPLE 272C for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 272E

This example was made by substituting EXAMPLE 272D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.74 (d, 1H), 8.60 (s, 1H),8.14 (dd, 1H), 7.63 (d, 2H), 7.49 (m, 1H), 7.35 (m, 6H), 7.25 (m, 3H),7.06 (m, 3H), 6.80 (d, 2H), 3.41 (s, 2H), 3.28 (m, 4H), 3.22 (s, 2H),2.47 (m, 4H), 1.01 (m, 4H).

EXAMPLE 273A

This example was prepared by substituting(1-hydroxymethyl-cyclohexyl)carbamic acid tert-butyl ester, prepared asdescribed in Bioorg. Med. Chem. Lett., 2003; 13; 1883, for(S)-2-amino-butan-1-ol in EXAMPLE 267A.

EXAMPLE 273B

This example was prepared by substituting EXAMPLE 273A for EXAMPLE 272Bin EXAMPLE 272C.

EXAMPLE 273C

This example was prepared by substituting EXAMPLE 273B for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 273D

This example was made by substituting EXAMPLE 273C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.71 (s, 1H), 8.63 (s, 1H),7.92 (d, 1H), 7.68 (m, 2H), 7.47 (m, 5H), 7.32 (m, 1H), 7.20 (m, 4H),6.94 (m, 6H), 6.78 (m, 1H), 4.38 (s, 2H), 3.56 (m, 4H), 3.38 (s, 2H),2.31 (m, 4H), 1.47 (m, 10H).

EXAMPLE 274A

This example was prepared by substituting (R)-2-amino-propan-1-ol for(S)-2-amino-butan-1-ol in EXAMPLE 267A.

EXAMPLE 274B

This example was prepared by substituting EXAMPLE 274A for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 274C

This example was made by substituting EXAMPLE 274B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.80 (br s, 1H), 8.42 (br s,1H), 8.03 (d, 1H), 7.65 (d, 2H), 7.50 (m, 1H), 7.34 (m, 9H), 7.22 (m,3H), 6.77 (d, 2H), 6.63 (m, 1H), 3.88 (m, 1H), 3.42 (s, 2H), 3.26 (m,4H), 3.10 (d, 2H), 2.48 (m, 4H), 1.43 (d, 3H).

EXAMPLE 275A

This example was prepared by substituting (S)-2-amino-propan-1-ol for(S)-2-amino-butan-1-ol in EXAMPLE 267A.

EXAMPLE 275B

This example was prepared by substituting EXAMPLE 275A for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 275C

This example was made by substituting EXAMPLE 275B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.82 (d, 1H), 8.45 (d, 1H),8.04 (dd, 1H), 7.64 (d, 2H), 7.56 (m, 1H), 7.35 (m, 10H), 7.20 (m, 3H),6.77 (d, 2H), 6.65 (d, 1H), 3.91 (m, 1H), 3.51 (s, 2H), 3.27 (t, 4H),3.12 (m, 2H), 2.48 (t, 4H), 1.45 (d, 3H).

EXAMPLE 276A

This example was prepared by substituting (1R,2R)-(2-hydroxycyclohexyl)carbamic acid tert-butyl ester, prepared asdescribed in Synth. Commun. 1992, 22, 3003, for (S)-2-amino-butan-1-olin EXAMPLE 267A.

This example was prepared by substituting EXAMPLE 276A for EXAMPLE 272Bin EXAMPLE 272C.

EXAMPLE 276C

This example was prepared by substituting EXAMPLE 276B for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 276D

This example was made by substituting EXAMPLE 276C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.92 (s, 1H), 8.78 (s, 1H),8.07 (d, 1H), 7.61 (m, 3H), 7.35 (m, 10H), 7.09 (m, 3H), 6.76 (m, 3H),3.84 (s, 1H), 3.65 (s, 1H), 3.48 (m, 2H), 3.25 (m, 4H), 2.47 (m, 4H),1.73 (m, 8H).

EXAMPLE 277

This example was made by substituting EXAMPLE 276C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.92 (d, 1H), 8.80 (d, 1H),8.08 (dd, 1H), 7.66 (d, 2H), 7.53 (m, 1H), 7.35 (m, 8H), 7.23 (m, 1H),7.11 (m, 3H), 6.78 (m, 3H), 3.87 (m, 1H), 3.65 (m, 1H), 3.46 (s, 2H),3.28 (m, 4H), 2.49 (m, 4H), 1.75 (m, 8H).

EXAMPLE 278A

This example was prepared by substituting(1S,2R)-(2-hydroxycyclohexyl)carbamic acid tert-butyl ester, prepared asdescribed in Eur. J. Org. Chem., 1998, 9, 1771, for(S)-2-amino-butan-1-ol in EXAMPLE 267A.

EXAMPLE 278B

This example was prepared by substituting EXAMPLE 278A for EXAMPLE 272Bin EXAMPLE 272C.

EXAMPLE 278C

This example was prepared by substituting EXAMPLE 278B for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 278D

This example was made by substituting EXAMPLE 278C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.93 (d, 1H), 8.80 (d, 1H),8.09 (dd, 1H), 7.64 (d, 2H), 7.53 (m, 1H), 7.35 (m, 8H), 7.12 (m, 3H),6.80 (m, 3H), 3.87 (m, 1H), 3.66 (m, 1H), 3.50 (s, 2H), 3.32 (m, 4H),2.50 (m, 4H), 1.85 (m, 8H).

EXAMPLE 279A

This example was prepared by substitutingS-(1-hydroxymethyl-2-pyridin-3-yl-ethyl)-carbamic acid tert-butyl esterfor (S)-2-amino-butan-1-ol in EXAMPLE 267A.

EXAMPLE 279B

This example was prepared by substituting EXAMPLE 279A for EXAMPLE 272Bin EXAMPLE 272C.

EXAMPLE 279C

This example was prepared by substituting EXAMPLE 279B for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 279D

This example was made by substituting EXAMPLE 795333C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.74 (d, 1H), 8.48 (m, 3H),7.97 (dd, 1H), 7.64 (d, 2H), 7.53 (m, 2H), 7.37 (m, 9H), 7.23 (m, 5H),6.75 (d, 2H), 6.53 (d, 1H), 4.00 (m, 1H), 3.50 (s, 2H), 3.26 (m, 5H),3.13 (d, 2H), 2.98 (m, 1H), 2.48 (m, 4H).

EXAMPLE 280

This example was made by substituting EXAMPLE 90C and EXAMPLE 279C forEXAMPLE 10 and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.90 (s, 1H),8.62 (s, 1H), 8.53 (s, 1H), 8.45 (d, 1H), 8.15 (d, 1H), 7.81 (d, 1H),7.69 (m, 3H), 7.34 (m, 9H), 7.19 (m, 4H), 6.90 (d, 2H), 6.54 (d, 1H),4.18 (m, 1H), 3.34 (m, 6H), 3.12 (s, 3H), 3.04 (m, 2H), 2.94 (s, 2H),1.61 (m, 2H),.1.45 (m, 2H).

EXAMPLE 281

This example was made by substituting EXAMPLE 278C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.95 (d, 1H), 8.79 (d, 1H),8.06 (dd, 1H), 7.69 (m, 3H), 7.41 (m, 8H), 7.24 (m, 1H), 7.11 (m, 3H),6.80 (d, 1H), 6.74 (d, 2H), 3.86 (m, 1H), 3.66 (m, 1H), 3.29 (m, 8H),2.52 (s, 2H), 2.07 (m, 1H), 1.81 (m, 5H), 1.51 (m, 2H).

EXAMPLE 282A

This example was prepared by substituting (1-amino-cyclopentyl)-methanoland bis(2-methyl-3-furyl)disulphide for (S)-2-amino-butan-1-ol andphenyl disulphide, respectively, in EXAMPLE 267A.

EXAMPLE 282B

This example was prepared by substituting EXAMPLE 282A for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 282C

This example was made by substituting EXAMPLE 282B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, CDCl₃) δ 8.82 (d, 1H), 8.68 (s, 1H),8.06 (dd, 1H), 7.65 (d, 2H), 7.53 (m, 1H), 7.33 (m, 7H), 6.91 (m, 1H),6.88 (s, 1H), 6.78 (d, 2H), 5.99 (d, 1H), 3.47 (s, 2H), 3.26 (m, 4H),3.18 (s, 2H), 2.46 (m, 4H), 2.14 (br s, 3H), 2.08 (m, 4H), 1.78 (m, 4H).

EXAMPLE 283

This example was made by substituting EXAMPLE 282B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, CDCl₃) δ 8.82 (d, 1H), 8.68 (s, 1H),8.07 (dd, 1H), 7.65 (d, 2H), 7.49 (m, 1H), 7.34 (m, 6H), 7.23 (m, 1H),6.90 (m, 2H), 6.79 (d, 2H), 6.00 (d, 1H), 3.41 (s, 2H), 3.26 (m, 4H),3.18 (s, 2H), 2.46 (m, 4H), 2.14 (s, 3H), 2.08 (m, 4H), 1.78 (m, 4H).

EXAMPLE 284

This example was made by substituting EXAMPLE 279C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.76 (d, 1H), 8.50 (m, 3H),7.98 (dd, 1H), 7.62 (d, 2H), 7.50 (m, 2H), 7.35 (m, 8H), 7.21 (m, 4H),6.78 (d, 2H), 6.53 (d, 1H), 4.01 (m, 1H), 3.42 (s, 2H), 3.27 (m, 5H),3.13 (d, 2H), 2.99 (m, 1H), 2.48 (m, 4H).

EXAMPLE 285A

This example was made by substituting 2-bromo-3-bromomethylpyridine,prepared as described in J. Am. Chem. Soc, 1985, 107, 7487, for2-bromobenzyl bromide in EXAMPLE 2A.

EXAMPLE 285B

This example was made by substituting EXAMPLE 285A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 285C

This example was made by substituting EXAMPLE 285B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 285D

This example was made by substituting EXAMPLE 285C for EXAMPLE 10 inEXAMPLE 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 8.70 (m, 1H),8.54 (d, 1H), 8.29 (d, 1H), 8.11 (m, 1H), 7.86 (dd, 1H), 7.76 (d, 2H),7.58 (m, 5H), 7.16 (m, 6H), 6.94 (d, 2H), 4.19 (m, 1H), 3.54 (m, 4H),3.39 (d, 2H), 3.13 (m, 4H), 2.75 (s, 3H), 2.74 (s, 3H), 2.49 (m, 4H),2.14 (m, 2H).

EXAMPLE 286

This example was made by substituting EXAMPLE 285C and3-nitro-4-(2-phenylsulfanylethylamino)benzenesulfonamide, prepared asdescribed in WO02/24636, For EXAMPLE 10 and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.83 (d, 1H),8.78 (d, 1H), 8.67 (t, 1H), 8.34 (d, 1H), 8.10 (dd, 1H), 7.67 (d, 1H),7.52 (m, 3H), 7.41 (m, 4H), 7.30 (m, 2H), 7.23 (m, 1H), 6.82 (d, 1H),6.73 (d, 2H), 4.35 (s, 2H), 3.57 (q, 2H), 3.47 (m, 4H), 3.20 (t, 2H),2.97 (m, 4H).

EXAMPLE 287

This example was made by substituting EXAMPLE 285C and4-(H1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (d, 1H),8.55 (d, 1H), 8.30 (d, 1H), 8.12 (m, 1H), 7.87 (dd, 1H), 7.76 (d, 2H),7.57 (m, 5H), 7.16 (m, 6H), 6.94 (d, 2H), 4.19 (m, 1H), 3.97 (d, 2H),3.58 (m, 7H), 3.38 (m, 5H), 3.19 (m, 4H), 3.01 (m, 4H), 2.17 (m, 2H).

EXAMPLE 288A

This example was made by substituting phenylboronic acid and EXAMPLE285A for 4-chlorophenylboronic acid and EXAMPLE 2A, respectively, inEXAMPLE 2B.

EXAMPLE 288B

This example was made by EXAMPLE 288A for EXAMPLE 2B in EXAMPLE 2C.

EXAMPLE 288C

This example was made by substituting EXAMPLE 288B and3-nitro-4-(2-phenylsulfanylethylamino)-benzenesulfonamide, prepared asdescribed in WO02/24636, for EXAMPLE 1C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively,in EXAMPLE 1D. ¹H NMR (300 MHz, CDCl₃) δ 8.86 (d, 1H), 8.65 (m, 2H),8.14 (dd, 1H), 7.91 (m, 1H), 7.60 (m, 4H), 7.43 (m, 5H), 7.28 (m, 4H),6.80 (m, 3H), 3.56 (m, 4H), 3.31 (m, 4H), 3.21 (t, 2H), 2.51 (m, 4H).

EXAMPLE 289

This example was made by substituting EXAMPLE 288B and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, CD₃OD) δ 8.67 (d, 1H),8.49 (dd, 1H), 8.07 (dd, 1H), 7.88 (dd, 1H), 7.78 (d, 2H), 7.48 (m, 6H),7.26 (m, 2H), 7.12 (m, 3H), 6.95 (d, 1H), 6.88 (d, 2H), 4.14 (m, 1H),3.66 (m, 4H), 3.53 (m, 2H), 3.25 (m, 6H), 2.51 (m, 10H), 2.13 (m, 1H),1.92 (m, 1H).

EXAMPLE 290

This example was made by substituting EXAMPLE 288B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (dd, 1H), 8.44 (d, 1H),8.31 (d, 1H), 7.94 (dd, 1H), 7.79 (dd, 1H), 7.72 (d, 2H), 7.62 (m, 2H),7.43 (m, 5H), 7.32 (m, 2H), 7.25 (m, 2H), 7.17 (m, 1H), 6.87 (d, 1H),6.79 (d, 2H), 4.05 (m, 1H), 3.50 (s, 2H), 3.30 (m, 2H), 3.16 (s, 4H),2.43 (m, 4H), 2.35 (m, 6H), 2.01 (m, 1H), 1.91 (m, 1H).

EXAMPLE 291A

This example was made by substituting 4-(methylsulfanyl)phenylboronicacid and EXAMPLE 285A for 4-chlorophenylboronic acid and EXAMPLE 2A,respectively, in EXAMPLE 2B.

EXAMPLE 291B

This example was made by substituting EXAMPLE 291A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 291C

This example was made by substituting EXAMPLE 291B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, CD₃OD) δ 8.74 (dd, 1H), 8.67 (d, 1H), 8.42(dd, 1H), 7.93 (dd, 1H), 7.74 (m, 3H), 7.50 (d, 2H), 7.44 (d, 2H), 7.22(m, 2H), 7.04 (m, 4H), 6.94 (d, 2H), 4.36 (s, 2H), 4.17 (m, 1H), 3.43(m, 5H), 3.24 (m, 3H), 3.04 (t, 4H), 2.87 (s, 6H), 2.51 (s, 3H), 2.24(m, 2H).

EXAMPLE 292A

This example was made by substituting 4-methoxyphenylboronic acid andEXAMPLE 285A for 4-chlorophenylboronic acid and EXAMPLE 2A,respectively, in EXAMPLE 2B.

EXAMPLE 292B

This example was made by substituting EXAMPLE 292A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 292C

This example was made by substituting EXAMPLE 292B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (dd, 1H), 8.45 (d, 1H),8.33 (d, 1H), 7.91 (dd, 1H), 7.78 (dd, 1H), 7.73 (d, 2H), 7.63 (d, 2H),7.33 (m, 3H), 7.21 (m, 3H), 7.01 (d, 2H), 6.86 (d, 1H), 6.80 (d, 2H),4.04 (m, 1H), 3.79 (s, 3H), 3.50 (s, 2H), 3.18 (s, 4H), 3.00 (d, 2H),2.68 (m, 2H), 2.45 (m, 4H), 2.33 (s, 6H), 1.95 (m, 2H).

EXAMPLE 293A

This example was made by substituting 4-dimethylaminophenylboronic acidand EXAMPLE 285A for 4-chlorophenylboronic acid and EXAMPLE 2A,respectively, in EXAMPLE 2B.

EXAMPLE 293B

This example was made by substituting EXAMPLE 293A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 293

This example was made by substituting EXAMPLE 293B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, CD₃OD) δ 8.66 (d, 1H), 8.46 (dd, 1H), 8.08(dd, 1H), 7.94 (dd, 1H), 7.75 (d, 2H), 7.42 (m, 3H), 7.24 (m, 2H), 7.08(m, 3H), 6.96 (d, 1H), 6.91 (d, 2H), 6.84 (d, 2H), 4.14 (m, 1H), 3.64(s, 2H), 3.38 (m, 4H), 3.23 (m, 4H), 3.00 (s, 6H), 2.86 (s, 7H), 2.54(m, 4H), 2.22 (m, 2H).

EXAMPLE 294A

This example was made by substituting 4-fluorophenylboronic acid andEXAMPLE 285A for 4-chlorophenylboronic acid and EXAMPLE 2A,respectively, in EXAMPLE 2B.

EXAMPLE 294B

This example was made by substituting EXAMPLE 294A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 294

This example was made by substituting EXAMPLE 294B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, CD₃OD) δ 8.74 (dd, 1H), 8.67 (d, 1H), 8.37(dd, 1H), 7.93 (dd, 1H), 7.73 (m, 3H), 7.60 (m, 2H), 7.31 (m, 2H), 7.22(m, 2H), 7.03 (m, 4H), 6.95 (d, 2H), 4.39 (s, 2H), 4.17 (m, 1H), 3.47(m, 4H), 3.38 (m, 1H), 3.23 (m, 3H), 3.08 (m, 4H), 2.86 (s, 6H), 2.24(m, 2H).

EXAMPLE 295A

This example was made by substituting 4-(methanesulphonyl)phenylboronicacid and EXAMPLE 285A for 4-chlorophenylboronic acid and EXAMPLE 2A,respectively, in EXAMPLE 2B.

EXAMPLE 295B

This example was made by substituting EXAMPLE 295A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 295C

This example was made by substituting EXAMPLE 295B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.62 (m, 3H), 8.02 (d, 2H), 7.89(m, 3H), 7.80 (m, 3H), 7.32 (m, 3H), 7.19 (m, 3H), 6.73 (m, 3H), 4.06(m, 1H), 3.46 (s, 2H), 3.24 (m, 4H), 3.12 (d, 2H), 2.85 (m, 3H), 2.59(s, 6H), 2.51 (m, 5H), 2.19 (m, 1H), 2.08 (m, 1H).

EXAMPLE 205A

This example was made by substituting 2-bromoethylamine hydrobromide forEXAMPLE 21C in EXAMPLE 21D.

EXAMPLE 296A

This example was made by substituting pyridin-4-yl-methanethiol for2-mercaptoimidazole in EXAMPLE 205B.

EXAMPLE 296B

This example was made by substituting3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.87 (d, 1H), 8.62 (m, 1H),8.42 (d, 2H), 8.19 (dd, 1H), 7.62 (d, 3H), 7.35 (m, 7H), 7.15 (d, 2H),6.92 (d, 1H), 6.77 (d, 2H), 3.70 (q, 2H), 3.54 (s, 2H), 3.32 (m, 6H),2.53 (m, 4H).

EXAMPLE 297A

This example was made by substituting 4-(methanesulphonyl)phenylboronicacid for 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 297B

This example was made by substituting EXAMPLE 297A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 297C

This example was made by substituting EXAMPLE 297B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.66 (d, 1H), 8.57 (d, 1H), 7.96(d, 2H), 7.80 (m, 3H), 7.66 (d, 2H), 7.49 (m, 1H), 7.38 (m, 2H), 7.29(m, 2H), 7.19 (m, 4H), 6.71 (m, 3H), 4.04 (m, 1H), 3.38 (s, 2H), 3.18(m, 4H), 3.10 (m, 6H), 2.85 (m, 2H), 2.58 (s, 6H), 2.45 (m, 4H), 2.20(m, 1H), 2.07 (m, 1H).

EXAMPLE 298

This example was made by substituting EXAMPLE 297B and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidefor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, 1H),8.29 (d, 1H), 8.01 (d, 2H), 7.87 (dd, 1H), 7.76 (d, 2H), 7.67 (d, 2H),7.55 (m, 2H), 7.37 (d, 1H), 7.23 (m, 2H), 7.15 (m, 4H), 6.93 (s, 2H),4.19 (m, 1H), 3.95 (s, 2H), 3.54 (m, 12H), 3.40 (d, 2H), 3.26 (s, 3H),3.19 (m, 4H), 3.02 (m, 2H), 2.17 (m, 2H).

EXAMPLE 299A

EXAMPLE 19C (0.938 g) in dichloromethane (10 mL) at 25° C. was treatedwith di(tert-butyl) dicarbonate (0.873 g), stirred for 24 hours, andconcentrated. The concentrate was flash chromatographed on silica gelwith 20-60% ethyl acetate/hexanes.

EXAMPLE 299B

This example was prepared by substituting EXAMPLE 299A for EXAMPLE 67Ain EXAMPLE 67B.

EXAMPLE 299C

This example was prepared by substituting EXAMPLE 299B for EXAMPLE 272Bin EXAMPLE 272C.

EXAMPLE 299D

This example was prepared by substituting EXAMPLE 299C for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 299E

EXAMPLE 299D (0.485 g) at 25° C. was treated with 1M borane·THF (8 mL),stirred for 16 hours, treated with methanol (5 mL), and concentrated.The concentrate was refluxed in methanol/12M HCl (30 mL/6 mL) for 8hours and concentrated. The concentrate was flash chromatographed onsilica gel with 1-20% methanol/NH₃-saturated dichloromethane.

EXAMPLE 299F

This example was prepared by substituting EXAMPLE 299E for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, CDCl₃) δ 8.80 (d, 1H), 8.41 (d, 1H), 8.07(dd, 1H), 7.77 (d, 2H), 7.63 (dd, 3H), 7.46 (m, 3H), 7.34 (m, 6H), 7.24(m, 1H), 7.00 (d, 1H), 6.78 (d, 2H), 4.54 (m, 1H), 3.69 (m, 4H), 3.45(d, 2H), 3.41 (s, 2H), 3.26 (m, 4H), 2.47 (m, 6H), 2.34 (m, 3H), 2.20(m, 2H), 1.86 (m, 2H).

EXAMPLE 300A

This example was made by substituting 4-dimethylaminophenylboronic acidfor 4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 300B

This example was made by substituting EXAMPLE 300A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 300C

This example was made by substituting EXAMPLE 300B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (d, 1H), 8.20 (d, 1H), 7.81(dd, 1H), 7.72 (m, 2H), 7.50 (m, 1H), 7.30 (m, 6H), 7.24 (m, 4H), 6.90(d, 1H), 6.79 (m, 4H), 4.07 (m, 1H), 3.43 (s, 2H), 3.21 (m, 8H), 2.92(s, 6H), 2.56 (s, 6H), 2.43 (m, 4H), 2.05 (m, 2H).

EXAMPLE 301A

This example was prepared by substituting EXAMPLE 18C for EXAMPLE 19C inEXAMPLE 299A.

EXAMPLE 301B

This example was prepared by substituting EXAMPLE 301A for EXAMPLE 67Ain EXAMPLE 67B.

EXAMPLE 301C

This example was prepared by substituting EXAMPLE 301B for EXAMPLE 272Bin EXAMPLE 272C.

EXAMPLE 301D

This example was prepared by substituting EXAMPLE 301C for EXAMPLE 21Cin EXAMPLE 21D.

EXAMPLE 301E

This example was made by substituting EXAMPLE 301D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (m, 2H), 7.90 (dd, 1H),7.76 (d, 2H), 7.58 (dd, 2H), 7.50 (m, 6H), 7.38 (m, 4H), 7.23 (m, 2H),6.90 (d, 2H), 4.70 (m, 1H), 4.17 (m, 1H), 3.76 (m, 1H), 3.43 (s, 2H),3.25 (m, 4H), 2.94 (m, 1H), 2.88 (s, 3H), 2.77 (m, 4H), 2.42 (m, 4H).

EXAMPLE 302A

This example was prepared by substituting3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester,prepared as described in J. Org. Chem., 1997, 62, 4197, for(S)-2-amino-butan-1-ol in EXAMPLE 267A.

EXAMPLE 302B

This example was made by substituting EXAMPLE 302A for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 302C

This example was made by substituting EXAMPLE 302B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 302D

This example was prepared by substituting EXAMPLE 302C for EXAMPLE 272Bin EXAMPLE 272C. ¹H NMR (300 MHz, CD₃OD) δ 8.78 (d, 1H), 7.94 (dd, 1H),7.74 (m, 3H), 7.55 (m, 7H), 7.36 (m, 7H), 6.96 (d, 2H), 6.75 (d, 1H),4.51 (m, 1H), 4.44 (s, 2H), 4.02 (m, 2H), 3.86 (q, 1H), 3.49 (m, 2H),3.43 (m, 2H), 3.35 (m, 2H), 3.14 (m, 4H).

EXAMPLE 303

This example was made by substituting pyridine-4-thiol forisopropylamine in EXAMPLE 35B. ¹H NMR (400 MHz, CD₃OD) δ 8.64 (m, 1H),8.23 (m, 2H), 7.83 (m, 3H), 7.50 (m, 1H), 7.36 (m, 7H), 7.23 (m, 5H),7.11 (m, 3H), 6.85 (d, 2H), 6.78 (d, 1H), 4.14 (m, 1H), 3.60 (m, 1H),3.47 (s, 2H), 3.21 (m, 6H), 3.10 (m, 1H), 2.46 (m, 4H), 2.26 (m, 1H),2.12 (m, 1H).

EXAMPLE 304A

A mixture of 3-bromo-4-methylpyridine (1.34 g) and NCS (1.43 g) in CCl₄(10 mL) at reflux was stirred for 21 hours and filtered. The filtratewas dried (MgSO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 0-30% ethyl acetate/hexanes.

EXAMPLE 304B

This example was prepared by substituting EXAMPLE 304A for 2-bromobenzylbromide in EXAMPLE 2A.

EXAMPLE 304C

This example was prepared by substituting EXAMPLE 304B for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 304D

This example was prepared by substituting EXAMPLE 304C for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 304E

This example was prepared by substituting EXAMPLE 304D for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.09 (d, 1H), 9.33 (d, 1H),8.69 (d, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.75 (m, 3H),7.57 (d, 2H), 7.48 (d, 2H), 7.17 (m, 6H), 6.94 (d, 2H), 4.18 (m, 1H),3.39 (d, 2H), 3.13 (m, 4H), 2.75 (m, 3H), 2.73 (m, 3H), 2.14 (m, 2H).

EXAMPLE 305

This example was prepared by substituting EXAMPLE 304D and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide for EXAMPLE2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, CDCl₃) δ 8.83 (d, 1H),8.75 (d, 1H), 8.66 (m, 2H), 8.11 (dd, 1H), 8.08 (d, 1H), 7.66 (d, 2H),7.51 (d, 2H), 7.40 (d, 2H), 7.27 (m, 5H), 6.81 (d, 1H), 6.78 (d, 2H),3.90 (s, 2H), 3.57 (m, 2H), 3.42 (m, 4H), 3.20 (t, 2H), 2.75 (m, 4H).

EXAMPLE 306A

2-Bromo-cyclopent-1-enecarbaldehyde, prepared as described in Collect.Czech. Chem. Commun., 1961, 26, 3059-3073, (1.5 g),4-piperazin-1-yl-benzoic acid ethyl ester (2 g) in ethanol (10 mL) at25° C. was treated with sodium cyanoborohydride (0.36 g), pH wasadjusted to 5-6 with acetic acid, stirred for 18 hours, filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 5-10% ethyl acetate/hexanes.

EXAMPLE 306B

This example was made by substituting EXAMPLE 306A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 306C

This example was made by substituting EXAMPLE 306B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 306D

This example was prepared by substituting EXAMPLE 306C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (m, 1H), 8.54 (d, 1H),8.28 (d, 1H), 7.86 (dd, 1H), 7.78 (d, 2H), 7.32 (d, 2H), 7.28 (d, 2H),7.22 (d, 2H), 7.14 (m, 4H), 6.97 (d, 2H), 4.18 (m, 1H), 3.90 (m, 4H),3.54 (m, 4H), 3.39 (d, 2H), 3.14 (m, 4H), 2.92 (m, 2H), 2.76 (s, 6H),2.64 (m, 2H), 2.15 (m, 2H), 1.96 (m, 2H).

EXAMPLE 307A

This example was prepared by substituting2-bromo-cyclohex-1-enecarbaldehyde, prepared as described in Collect.Czech. Chem. Commun., 1961, 26, 3059, for2-bromo-cyclopent-1-enecarbaldehyde in EXAMPLE 306A.

EXAMPLE 307B

This example was made by substituting EXAMPLE 307A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 307C

This example was made by substituting EXAMPLE 307B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 307D

This example was made by substituting EXAMPLE 307C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, 1H), 8.03 (d, 1H), 7.61(dd, 1H), 7.53 (d, 2H), 7.15 (d, 2H), 6.97 (m, 2H), 6.89 (m, 6H), 6.70(d, 2H), 3.93 (m, 1H), 3.37 (m, 4H), 3.13 (m, 4H), 2.89 (m, 4H), 2.49(s, 6H), 2.24 (s, 2H), 1.98 (d, 4H), 1.89 (q, 2H), 1.43 (m, 4H).

EXAMPLE 308A

This example was made by substituting EXAMPLE 306A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 308B

This example was made by substituting EXAMPLE 308A for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 8.50 (d, 1H), 8.25(d, 1H), 7.83 (dd, 1H), 7.77 (d, 2H), 7.17 (m, 3H), 7.09 (m, 4H), 6.98(d, 2H), 4.14 (m, 1H), 3.80 (s, 2H), 3.35 (d, 2H), 3.28 (m, 4H), 3.11(m, 4H), 2.70 (s, 6H), 2.64 (m, 2H), 2.41 (m, 2H), 2.10 (q, 2H), 1.93(m, 2H).

EXAMPLE 79

This example was made by substituting EXAMPLE 307C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidefor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d, 1H),8.37 (d, 1H), 7.80 (dd, 1H), 7.72 (d, 2H), 7.37 (d, 2H), 7.28 (m, 2H),7.17 (m, 5H), 7.04 (d, 1H), 6.85 (d, 2H), 4.14 (s, 1H), 3.53 (m, 4H),3.36 (m, 4H), 3.21 (m, 4H), 2.80 (s, 2H), 2.45 (m, 2H), 2.34 (m, 5H),2.19 (m, 5H), 2.01 (m, 1H), 1.87 (m, 1H), 1.67 (m, 4H).

EXAMPLE 310

This example was made by substituting EXAMPLE 307C and EXAMPLE 18F forEXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (d, 1H),7.63 (m, 3H), 7.24 (m, 6H), 7.12 (m, 1H), 7.02 (d, 2H), 6.70 (d, 2H),6.58 (d, 1H), 5.74 (s, 1H), 3.76 (m, 1H), 3.16 (m, 6H), 3.07 (m, 4H),2.90 (m, 2H), 2.68 (s, 2H), 2.41 (m, 2H), 2.19 (m, 4H), 2.10 (m, 4H),1.95 (m, 2H), 1.57 (m, 4H).

EXAMPLE 311A

This example was made by substituting EXAMPLE 307A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 311B

This example was made by substituting EXAMPLE 311A for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, 1H), 8.29 (d, 1H), 7.87(dd, 1H), 7.81 (d, 2H), 7.21 (m, 3H), 7.12 (m, 3H), 7.03 (d, 2H), 4.19(m, 1H), 3.89 (s, 2H), 3.30 (m, 8H), 3.15 (m, 4H), 2.74 (s, 6H), 2.56(m, 2H), 2.25 (m, 2H), 2.15 (q, 2H), 1.68 (m, 4H).

EXAMPLE 312A

A mixture of DMF (10 mL) and chloroform (200 mL) at 5° C. was treatedwith PBr₃ (10 mL), stirred at 25° C. for 40 minutes, treated withtetrahydropyran-4-one (5 g) in chloroform (50 mL) at 0° C., stirred at25° C. for 18 hours, poured onto ice, treated with sodium bicarbonate,and extracted with diethyl ether. The extract was washed with saturatedsodium bicarbonate and brine and dried (MgSO₄), filtered andconcentrated. The concentrate was flash chromatographed on silica gelwith 10% ethyl acetate/hexanes.

EXAMPLE 312B

This example was prepared by substituting 312A for2-bromo-cyclopent-1-enecarbaldehyde in EXAMPLE 306A.

EXAMPLE 312C

This example was made by substituting EXAMPLE 312B for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 312D

This example was made by substituting EXAMPLE 312C for. EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 312E

This example was made by substituting EXAMPLE 312D for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.29 (d, 1H), 8.03 (d, 1H), 7.61(dd, 1H), 7.52 (d, 2H), 7.19 (d, 2H), 6.98 (m, 4H), 6.89 (m, 4H), 6.70(d, 2H), 3.99 (s, 2H), 3.93 (m, 1H), 3.69 (s, 2H), 3.58 (t, 2H), 3.13(s, 8H), 2.88 (m, 4H), 2.49 (s, 6H), 2.12 (m, 2H), 1.89 (q, 2H).

EXAMPLE 313A

This example was made by substituting EXAMPLE 312B and4-methoxyphenylboronic acid for EXAMPLE 2A and 4-chlorophenylboronicacid, respectively, in EXAMPLE 2B.

EXAMPLE 313B

This example was made by substituting EXAMPLE 313A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 313

This example was made by substituting EXAMPLE 313B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (d, 1H), 8.28 (d, 1H), 7.87(dd, 1H), 7.78 (d, 2H), 7.23 (m, 2H), 7.14 (m, 4H), 7.05 (d, 2H), 6.95(d, 2H), 6.91 (d, 2H), 4.19 (m, 1H), 3.86 (m, 2H), 3.73 (s, 3H), 3.60(m, 4H), 3.39 (d, 2H), 3.15 (m, 4H), 2.74 (m, 8H), 2.26 (s, 2H), 2.20(s, 2H), 2.15 (q, 2H), 1.70 (s, 4H).

EXAMPLE 314A

This example was made by substituting EXAMPLE 312B and4-fluorophenylboronic acid for EXAMPLE 2A and 4-chlorophenylboronicacid, respectively, in EXAMPLE 2B.

EXAMPLE 313B

This example was made by substituting EXAMPLE 314A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 314C

This example was made by substituting EXAMPLE 313B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, 1H), 8.29 (d, 1H), 7.87(dd, 1H), 7.79 (d, 2H), 7.23 (m, 2H), 7.15 (m, 8H), 6.96 (d, 2H), 4.19(m, 1H), 3.86 (m, 4H), 3.60 (s, 2H), 3.39 (d, 2H), 3.15 (m, 4H), 2.77(m, 8H), 2.27 (s, 2H), 2.22 (s, 2H), 2.15 (q, 2H), 1.72 (s, 4H).

EXAMPLE 315A

This example was made by substituting EXAMPLE 307A and phenylboronicacid for EXAMPLE 2A and 4-chlorophenylboronic acid, respectively, inEXAMPLE 2B.

EXAMPLE 315B

This example was made by substituting EXAMPLE 315A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 315C

This example was made by substituting EXAMPLE 315B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, 1H), 8.29 (d, 1H), 7.87(dd, 1H), 7.78 (d, 2H), 7.36 (m, 2H), 7.28 (m, 1H), 7.21 (m, 2H), 7.13(m, 6H), 6.95 (d, 2H), 4.19 (s, 1H), 3.87 (s, 2H), 3.62 (m, 4H), 3.39(d, 2H), 3.15 (m, 4H), 2.74 (m, 8H), 2.29 (s, 2H), 2.22 (s, 2H), 2.14(q, 2H), 1.72 (m, 4H).

EXAMPLE 316A

This example was prepared by substituting2-bromo-cyclooct-1-enecarbaldehyde for2-bromo-cyclopent-1-enecarbaldehyde in EXAMPLE 306A.

EXAMPLE 316B

This example was made by substituting EXAMPLE 316A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 316C

This example was made by substituting EXAMPLE 316B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 316D

This example was made by substituting EXAMPLE 316C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (d, 1H), 8.30 (d, 1H), 7.86(dd, 1H), 7.78 (d, 2H), 7.43 (d, 2H), 7.17 (m, 8H), 6.95 (d, 2H), 4.19(m, 5H), 3.89. (m, 2H), 3.64 (s, 2H), 3.39 (m, 4H), 3.13 (m, 4H), 2.75(s, 3H), 2.74 (s, 3H), 2.46 (m, 2H), 2.14 (q, 2H), 1.66 (m, 2H), 1.54(m, 4H), 1.41 (m, 2H).

EXAMPLE 317A

This example was made by substituting EXAMPLE 312B and4-methylthiophenylboronic acid for EXAMPLE 2A and 4-chlorophenylboronicacid, respectively, in EXAMPLE 2B.

EXAMPLE 317B

This example was made by substituting EXAMPLE 317A for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 317C

This example was made by substituting EXAMPLE 317B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (d, 1H), 8.29 (d, 1H), 7.86(dd, 1H), 7.79 (d, 2H), 7.22 (m, 4H), 7.11 (m, 6H), 6.95 (d, 2H), 4.17(m, 1H), 3.90 (m, 4H), 3.65 (m, 4H), 3.39 (d, 2H), 3.12 (m, 4H), 2.75(s, 3H), 2.74 (s, 3H), 2.45 (s, 3H), 2.24 (m, 4H), 2.14 (q, 2H), 1.71(m, 4H).

EXAMPLE 318A

This example was prepared by substituting2-bromo-cyclohept-1-enecarbaldehyde for2-bromo-cyclopent-1-enecarbaldehyde in EXAMPLE 306A.

EXAMPLE 318B

This example was made by substituting EXAMPLE 318A for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 318C

This example was made by substituting EXAMPLE 318B for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 318D

This example was made by substituting EXAMPLE 318C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, 1H), 8.29 (d, 1H), 7.86(dd, 1H), 7.78 (d, 2H), 7.40 (d, 2H), 7.22 (m, 2H), 7.14 (m, 6H), 6.95(d, 2H), 4.19 (m, 1H), 3.87 (s, 2H), 3.61 (m, 2H), 3.39 (m, 4H), 3.15(m, 4H), 2.75 (m, 8H), 2.46 (m, 4H), 2.14 (m, 2H), 1.80 (m, 2H), 1.56(m, 4H).

EXAMPLE 319

This example was made by substituting EXAMPLE 318C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidefor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, 1H),8.29 (d, 1H), 7.87 (dd, 1H), 7.78 (d, 2H), 7.40 (d, 2H), 7.22 (m, 3H),7.14 (m, 6H), 6.93 (d, 2H), 4.20 (m, 1H), 3.91 (m, 4H), 3.39 (m, 6H),3.18 (m, 6H), 3.03 (m, 2H), 2.79 (m, 2H), 2.45 (m, 4H), 2.16 (q, 2H),1.81 (m, 2H), 1.56 (m, 4H).

EXAMPLE 320A

This example was made by substituting 4,4-dimethyl-cyclohexanone fortetrahydro-pyran-4-one in EXAMPLE 312A.

EXAMPLE 320B

This example was prepared by substituting 320A for2-bromo-cyclopent-1-enecarbaldehyde in EXAMPLE 306A.

EXAMPLE 320C

This example was made by substituting EXAMPLE 320B for EXAMPLE 2A inEXAMPLE 2B.

EXAMPLE 320D

This example was made by substituting EXAMPLE 320C for EXAMPLE 2B inEXAMPLE 2C.

EXAMPLE 320E

This example was made by substituting EXAMPLE 320D for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, 1H), 8.28 (d, 1H), 7.86(dd, 1H), 7.79 (d, 2H), 7.41 (m, 2H), 7.23 (m, 2H), 7.14 (m, 6H), 6.95(d, 2H), 4.19 (m, 1H), 3.90 (m, 1H), 3.39 (d, 2H), 3.15 (s, 6H), 2.74(m, 8H), 2.54 (m, 3H), 2.28 (m, 2H), 2.14 (q, 2H), 2.03 (s, 2H), 1.47(t, 2H), 0.98 (s, 6H).

EXAMPLE 321

This example was made by substituting EXAMPLE 320D and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidefor EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, 1H),8.29 (d, 1H), 7.87 (dd, 1H), 7.78 (d, 2H), 7.41 (m, 2H), 7.22 (m, 2H),7.14 (m, 6H), 6.95 (d, 2H), 4.20 (m, 1H), 3.93 (m, 2H), 3.57 (m, 4H),3.39 (m, 6H), 3.19 (m, 4H), 3.02 (m, 2H), 2.81 (m, 2H), 2.53 (s, 2H),2.27 (m, 2H), 2.17 (q, 2H), 2.01 (s, 2H), 1.47 (t, 2H), 0.98 (s, 6H).

EXAMPLE 322A

A mixture of EXAMPLE 32A (1 g) and 60% oily sodium hydride (0.30 g) intoluene (15 mL) was refluxed for 1 hour, treated with4-(2-chloroethyl)morpholine (2 g), refluxed for 18 hours, treated withaqueous NH₄Cl and extracted with ethyl acetate. The extract was washedwith water and brine and dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 5-15% 7M NH₃ inmethanol/dichloromethane.

EXAMPLE 322B

This example was made by substituting EXAMPLE 322A and phenylboronicacid for EXAMPLE 32B and 4-chlorophenylboronic acid, respectively, inEXAMPLE 32C.

EXAMPLE 322C

This example was made by substituting EXAMPLE 322B for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 322D

This example was made by substituting EXAMPLE 322C and4-(1,1-dimethyl-2-phenylsulfanylethylamino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H),11.08 (m, 1H), 10.02 (m, 1H), 8.30 (s, 1H), 8.28 (d, 1H), 7.98 (t, 2H),7.61 (dd, 1H), 7.50 (d, 2H), 7.11 (m, 8H), 6.75 (m, 5H), 6.63 (d, 1H),3.67 (m, 6H), 3.12 (m, 4H), 2.79 (m, 10H), 1.52 (m, 4H), 1.34 (s, 6H).

EXAMPLE 323

This example was made by substituting EXAMPLE 322C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H),11.16 (m, 1H), 10.08 (m, 1H), 8.53 (t, 1H), 8.36 (d, 1H), 7.68 (dd, 1H),7.47 (d, 2H), 7.07 (m, 16H), 6.62 (d, 1H), 3.55 (m, 4H), 3.45 (m, 4H),2.95 (m, 12H), 1.52 (m, 2H), 1.26 (m, 2H), 1.00 (m, 2H).

EXAMPLE 324A

This example was made by substituting 1-(2-chloroethyl)pyrrolidine for4-(2-chloroethyl)morpholine in EXAMPLE 322A.

EXAMPLE 324B

This example was made by substituting EXAMPLE 324A and phenylboronicacid for EXAMPLE 32B and 4-chlorophenylboronic acid, respectively, inEXAMPLE 32C.

EXAMPLE 324C

This example was made by substituting EXAMPLE 324B for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 324D

This example was made by substituting EXAMPLE 324C and4-(1,1-dimethyl-2-phenylsulfanylethylamino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.96 (s, 1H),10.39 (m, 1H), 8.50 (d, 2H), 7.82 (dd, 1H), 7.71 (d, 2H), 7.33 (m, 10H),7.16 (dd, 1H), 6.99 (t, 2H), 6.91 (t, 1H), 6.82 (d, 2H), 3.62 (m, 2H),3.38 (m, 6H), 3.28 (m, 2H), 2.96 (m, 6H), 1.93 (m, 2H), 1.82 (m, 2H),1.55 (s, 6H), 1.48 (m, 2H), 1.20 (m, 2H).

EXAMPLE 325

This example was made by substituting EXAMPLE 324C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.95 (s, 1H),10.46 (m, 1H), 8.74 (t, 1H), 8.58 (d, 1H), 7.90 (m, 1H), 7.67 (d, 2H),7.28 (m, 14H), 6.81 (d, 2H), 3.66 (m, 2H), 3.38 (m, 6H), 3.27 (m, 4H),2.98 (m, 6H), 1.93 (m, 2H), 1.82 (m, 2H), 1.48 (m, 2H), 1,19 (m, 2H).

EXAMPLE 326

This example was made by substituting EXAMPLE 324C and EXAMPLE 264B forEXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR 500 MHz, DMSO-d₆) δ 11.97 (s, 1H),10.65 (m, 1H), 8.47 (s, 1H), 8.41 (d, 1H), 7.82 (dd, 1H), 7.73 (d, 2H),7.27 (m, 10H), 6.81 (m, 6H), 3.63 (m, 2H), 3.35 (m, 6H), 2.96 (m, 6H),1.90 (m, 12H), 1.48 (m, 2H), 1.20 (m, 2H).

EXAMPLE 327A

This example was made by substituting 2-(dimethylamino)ethyl chloridefor 4-(2-chloroethyl)morpholine in EXAMPLE 322A.

EXAMPLE 327B

This example was made by substituting EXAMPLE 327A and phenylboronicacid for EXAMPLE 32B and 4-chlorophenylboronic acid, respectively, inEXAMPLE 32C.

EXAMPLE 327C

This example was made by substituting EXAMPLE 327B for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 327D

This example was made by substituting EXAMPLE 327C and4-(1,1-dimethyl-2-phenylsulfanylethylamino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.75 (s, 1H),10.00 (m, 1H), 8.29 (s, 1H), 8.27 (d, 1H), 7.60 (dd, 1H), 7.49 (d, 2H),7.10 (m, 10H), 6.93 (d, 1H), 6.77 (t, 2H), 6.68 (t, 1H), 6.60 (d, 2H),3.63 (m, 2H), 3.29 (m, 6H), 2.85 (m, 6H), 1.51 (m, 1H), 1.33 (s, 6H),1.25 (m, 2H), 1.08 (m, 1H), 1.0 (m, 2H).

EXAMPLE 328

This example was made by substituting EXAMPLE 327C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.71 (s, 1H),9.86 (m, 1H), 8.51 (t, 1H), 8.35 (s, 1H), 7.65 (dd, 1H), 7.44 (d, 2H),7.15 (m, 14H), 6.58 (d, 2H), 3.43 (m, 2H), 3.13 (m, 2H), 3.13 (t, 2H),3.03 (m, 6H), 2.76 (m, 6H), 1.51 (m, 1H), 1.24 (m, 2H), 0.97 (m, 2H).

EXAMPLE 329

This example was made by substituting EXAMPLE 327C and EXAMPLE 264B forEXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.72 (s, 1H),9.75 (m, 1H), 8.23 (s, 1H), 8.17 (d, 1H), 7.58 (dd, 1H), 7.11 (m, 10H),6.94 (d, 1H), 6.90 (d, 2H), 6.58 (d, 2H), 6.57 (d, 1H), 3.38 (m, 2H),3.15 (m, 2H), 2.98 (m, 2H), 2.74 (m, 4H), 2.50 (s, 3H), 2.49 (s, 3H),1.85 (m, 4H), 1.76 (m, 4H), 1.47 (m, 2H), 1.24 (m, 2H), 0.97 (m, 2H).

EXAMPLE 330A

This example was made by substituting 1-(2-chloroethyl)piperidine for4-(2-chloroethyl)morpholine in EXAMPLE 322A.

EXAMPLE 330B

This example was made by substituting. EXAMPLE 330A and phenylboronicacid for EXAMPLE 32B and 4-chlorophenylboronic acid, respectively, inEXAMPLE 32C.

EXAMPLE 330C

This example was made by substituting EXAMPLE 330B for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 330D

This example was made by substituting EXAMPLE 330C and4-(1,1-dimethyl-2-phenylsulfanylethylamino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D.

¹H NMR (500 MHz, DMSO-d₆) δ 11.97 (s, 1H), 10.27 (m, 1H), 8.51 (s, 1H),8.49 (d, 1H), 7.82 (dd, 1H), 7.72 (d, 2H), 7.33 (m, 10H), 7.16 (d, 1H),6.99 (t, 2H), 6.91 (t, 1H), 6.82 (d, 2H), 3.37 (m, 2H), 3.17 (m, 2H),3.03 (s, 2H), 2.95 (m, 8H), 1.73 (m, 6H), 1.55 (s, 6H), 1.50 (m, 2H),1.30 (m, 2H), 1.19 (m, 2H).

EXAMPLE 331

This example was made by substituting EXAMPLE 330C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D.

¹H NMR (500 MHz, DMSO-d₆) δ 11.95 (s, 1H), 10.16 (m, 1H), 8.74 (t, 1H),8.58 (s, 1H), 7.89 (dd, 1H), 7.67 (d, 2H), 7.29 (m, 14H), 6.81 (d, 2H),3.66 (m, 2H), 3.37 (m, 2H), 3.27 (t, 2H), 3.17 (m, 2H), 2.95 (m, 8H),1.73 (m, 4H), 1.63 (m, 2H), 1.49 (m, 2H), 1.30 (m, 2H), 1.19 (m, 2H).

EXAMPLE 332

This example was made by substituting EXAMPLE 330C and EXAMPLE 264B forEXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.97 (s, 1H),10.27 (m, 1H), 8.47 (s, 1H), 8.40 (d, 1H), 7.82 (dd, 1H), 7.74 (d, 2H),7.27 (m, 13H), 6.80 (m, 3H), 3.67 (m, 2H), 3.37 (m, 2H), 3.17 (m, 2H),3.03 (s, 2H), 2.92 (m, 6H), 2.09 (m, 2H), 1.98 (m, 2H), 1.70 (m, 10H),1.49 (m, 2H), 1.30 (m, 2H), 1.19 (m, 2H).

EXAMPLE 333A

This example was prepared by substituting(S)-3-(benzyloxycarbonyl)aminobutyrolactone, prepared as described in J.Am. Chem. Soc. 1986, 108, 4943-4952, for(R)-3-(benzyloxycarbonyl)aminobutyrolactone in EXAMPLE 19A.

EXAMPLE 333B

This example was prepared by substituting EXAMPLE 333A for EXAMPLE 18Ain EXAMPLE 18B.

EXAMPLE 333C

This example was prepared by substituting EXAMPLE 333B for EXAMPLE 18Bin EXAMPLE 18C.

EXAMPLE 333D

This example was prepared by substituting EXAMPLE 333C for EXAMPLE 19Cin EXAMPLE 19D.

EXAMPLE 333E

This example was prepared by substituting EXAMPLE 333D for EXAMPLE 18Cin EXAMPLE 18E.

EXAMPLE 333F

This example was made by substituting EXAMPLE 1C and EXAMPLE 333E forEXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.86 (s, 1H),11.20 (m, 1H), 11.07 (m, 1H), 9.97 (m, 1H), 8.30 (d, 1H), 8.05 (2, 1H),7.87 (dd, 1H), 7.60 (t, 1H), 7.53 (d, 2H), 7.06 (m, 13H), 6.69 (d, 2H),4.12 (s, 2H), 3.62 (m, 4H), 3.11 (m, 5H), 2.95 (m, 4H), 2.78 (m, 8H),1.51 (m, 2H).

EXAMPLE 334A

This example was made by substituting 4-hydoxyphenylboronic acid for4-chlorophenylboronic acid in EXAMPLE 2B.

EXAMPLE 334B

A mixture of EXAMPLE 334A (0.24 g), 2-(dimethylamino)ethyl chloride(0.22 g), and K₂CO₃ (0.5 g) in acetone (20 mL) at reflux was stirred for18 hours, concentrated, and treated with ethyl acetate and water. Theextract was washed with water and brine and dried (Na₂SO₄), filtered,and concentrated. The concentrate was flash chromatographed on silicagel with 5% 7M NH₃ in methanol/dichloromethane.

EXAMPLE 334C

This example was made by substituting EXAMPLE 334B for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 334D

This example was made by substituting EXAMPLE 334C for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (s, 1H), 11.55 (m, 1H),10.88 (m, 1H), 10.70 (m, 1H), 8.54 (d, 1H), 8.29 (d, 1H), 8.11 (dd, 1H),7.78 (d, 2H), 7.49 (t, 2H), 7.20 (m, 10H), 6.93 (d, 2H), 4.42 (t, 2H),4.36 (s, 2H), 4.29 (m, 1H), 3.86 (m, 2H), 3.52 (m, 2H), 3.39 (m, 2H),3.13 (m, 6H), 2.82 (s, 3H), 2.83 (s, 3H), 2.70 (m, 8H), 2.20 (m, 2H).

EXAMPLE 335

This example was made by substituting EXAMPLE 334C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (s, 1H),11.37 (m, 1H), 11.19 (m, 1H), 10.71 (m, 1H), 8.53 (d, 1H), 8.29 (d, 1H),8.06 (dd, 1H), 7.85 (dd, 2H), 7.78 (d, 2H), 7.50 (t, 2H), 7.20 (m, 10H),6.93 (d, 2H), 4.41 (t, 2H), 4.36 (s, 2H), 4.28 (m, 1H), 3.92 (m, 2H),3.80 (t, 2H), 3.52 (m, 2H), 3.39 (m, 2H), 3.23 (m, 8H), 2.98 (m, 2H),2.84 (s, 6H), 2.25 (m, 2H).

EXAMPLE 336

This example was made by substituting EXAMPLE 334C and4-(1,1-dimethyl-2-phenylsulfanylethylamino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (s, 1H),11.47 (m, 1H), 10.83 (m, 1H), 10.23 (m, 1H), 8.53 (s, 1H), 8.51 (d, 1H),8.10 (m, 1H), 7.83 (dd, 1H), 7.80 (d, 2H), 7.50 (t, 2H), 7.39 (d, 1H),7.31 (m, 3H), 7.25 (d, 2H), 7.10 (d, 2H), 7.01 (t, 2H), 6.93 (m, 3H),4.41 (t, 2H), 4.36 (s, 2H), 3.86 (m, 2H), 3.38 (m, 2H), 3.20 (s, 2H),3.23 (m, 2H), 2.98 (m, 2H), 3.01 (m, 4H), 2.84 (d, 3H), 2.73 (d, 3H),1.56 (s, 6H).

EXAMPLE 337

This example was made by substituting EXAMPLE 334C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (s, 1H),11.39 (m, 1H), 10.73 (m, 1H), 10.13 (m, 1H), 8.76 (t, 1H), 8.60 (d, 1H),8.07 (m, 1H), 7.91 (dd, 1H), 7.76 (d, 2H), 7.50 (t, 2H), 7.25 (m, 10H),7.09 (d, 2H), 6.92 (d, 2H), 4.41 (t, 2H), 4.36 (s, 2H), 3.86 (m, 2H),3.67 (m, 2H), 3.28 (m, 2H), 3.20 (s, 2H), 3.01 (m, 4H), 2.84 (d, 3H),2.73 (d, 3H).

EXAMPLE 338A

This example was made by substituting 4-(2-chloroethyl)morpholine for2-(dimethylamino)ethyl chloride in EXAMPLE 334B.

EXAMPLE 338B

This example was made by substituting EXAMPLE 338A for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 338C

This example was made by substituting EXAMPLE 338B for EXAMPLE 2C inEXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.89 (s, 1H), 11.50 (m, 1H),11.30 (m, 1H), 10.46 (m, 1H), 8.31 (d, 1H), 8.06 (d, 1H), 7.88 (m, 1H),7.55 (d, 2H), 7.27 (t, 2H), 6.98 (m, 11H), 6.70 (d, 2H), 4.28 (t, 2H),4.13 (s, 2H), 3.68 (m, 4H), 3.33 (m, 2H), 3.28 (m, 2H), 3.06 (m, 6H),2.78 (m, 6H), 2.48 (m, 6H), 1.97 (m, 2H).

EXAMPLE 339

This example was made by substituting EXAMPLE 338B and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.88 (s, 1H),11.47 (m, 1H), 11.28 (m, 1H), 11.13 (m 1H), 10.01 (m, 1H), 8.30 (d, 1H),8.05 (d, 1H), 7.87 (m, 1H), 7.61 (dd, 1H), 7.54 (d, 2H), 7.26 (t, 2H),6.96 (m, 11H), 6.70 (d, 2H), 4.26 (t, 2H), 4.12 (s, 2H), 4.07 (m, 1H),3.63 (m, 6H), 3.33 (m, 2H), 3.27 (m, 2H), 3.05 (m, 6H), 2.79 (m, 8H),1.52 (m, 2H).

EXAMPLE 340

This example was made by substituting EXAMPLE 338B and4-(1,1-dimethyl-2-phenylsulfanylethylamino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (s, 1H),11.83 (m, 1H), 11.62 (m, 1H), 10.43 (m, 1H), 8.53 (s, 1H), 8.51 (d, 1H),8.12 (m, 1H), 7.83 (dd, 1H), 7.80 (d, 2H), 7.49 (t, 2H), 7.39 (d, 1H),7.31 (m, 3H), 7.25 (d, 2H), 7.10 (d, 2H), 6.99 (t, 2H), 6.93 (m, 3H),4.51 (t, 2H), 4.36 (s, 2H), 3.91 (m, 2H), 3.35 (m, 8H), 3.02 (m, 8H),1.56 (s, 6H).

EXAMPLE 341

This example was made by substituting EXAMPLE 338B and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (s, 1H),11.67 (m, 1H), 11.46 (m, 1H), 10.24 (m, 1H), 8.76 (t, 1H), 8.60 (d, 1H),8.10 (m, 1H), 7.91 (dd, 1H), 7.76 (d, 2H), 7.50 (t, 2H), 7.26 (m, 10H),7.10 (d, 2H), 6.92 (d, 2H), 4.50 (t, 2H), 4.36 (s, 2H), 3.91 (m, 4H),3.35 (m, 10H), 3.01 (m, 8H).

EXAMPLE 342A

A mixture of EXAMPLE 30B (1.2 g) and pyridine (3 mL) in dichloromethane(10 mL) at 25° C. was treated with p-toluenesulfonyl chloride (0.572 g),stirred for 18 hours, treated with dichloromethane (150 mL), washed with5% HCl, water, and brine, and dried (Na₂SO₄), filtered, andconcentrated.

EXAMPLE 342B

A mixture of EXAMPLE 342A (1.7 g) and imidazole (0.42 g) in DMF (25 mL)at 60° C. was stirred for 4 hours, treated with ethyl acetate (200 mL),washed with aqueous NH₄Cl, water, and brine, and dried (Na₂SO₄),filtered, and concentrated. The concentrate was flash chromatographed onsilica gel with 50% ethyl acetate/hexane and 5%methanol/dichloromethane.

EXAMPLE 342C

This example was made by substituting EXAMPLE 342B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.47 (d, 1H), 8.17 (d, 1H),7.73 (m, 3H), 7.65 (s, 1H), 7.51 (dd, 1H), 7.37 (m, 2H), 7.19 (m, 10H),6.93 (s, 1H), 6.82 (d, 2H), 6.63 (d, 1H), 4.09 (t, 2H), 3.87 (m, 1H),3.31 (m, 8H), 3.15 (m, 4H), 2.23 (m, 2H).

EXAMPLE 343

This example was made by substituting EXAMPLE 342B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (m, 1H), 9.06 (m, 1H),8.53 (d, 1H), 8.23 (m, 2H), 8.08 (m, 1H), 7.82 (dd, 1H), 7.78 (d, 2H),7.71 (t, 1H), 7.70 (d, 2H), 7.64 (t, 2H), 7.43 (m, 8H), 7.06 (m, 4H),4.35 (s, 2H), 4.31 (t, 2H), 4.08 (m, 1H), 3.83 (m, 2H), 3.28 (m, 6H),2.76 (m, 2H), 2.39 (m, 2H).

EXAMPLE 344

This example was made by substituting EXAMPLE 90C and EXAMPLE 342B forEXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (m, 1H),9.06 (m, 2H), 8.53 (d, 2H), 8.22 (m, 2H), 7.82 (dd, 1H), 7.71 (m, 4H),7.64 (t, 1H), 7.26 (m, 10H), 6.99 (t, 2H), 6.83 (d, 1H), 4.31 (t, 2H),4.04 (m, 1H), 3.37 (m, 5H), 3.19 (s, 3H), 2.89 (m, 3H), 2.39 (m, 2H),1.46 (m, 2H), 1.17 (m, 2H).

EXAMPLE 345

This example was made by substituting(R)-4-(4-(4-methylpiperazin-1-yl)-1-phenylsulfanylmethyl-butylamino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.12 (m, 1H), 10.89 (m, 1H),8.53 (d, 1H), 8.30 (d, 1H), 8.05 (m, 1H), 7.86 (dd, 1H), 7.78 (d, 2H),7.54 (m, 3H), 7.24 (m, 10H), 6.93 (d, 2H), 4.35 (s, 2H), 4.16 (m, 1H),3.90 (m, 2H), 3.29 (m, 8H), 2.80 (m, 8H).

EXAMPLE 346

This example was made by substituting4-(((1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrobenzenesulfonamide(prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.14 (m, 1H), 11.09 (m, 1H),8.49 (d, 1H), 8.34 (d, 1H), 8.08 (m, 1H), 7.86 (dd, 1H), 7.78 (d, 2H),7.54 (m, 3H), 7.24 (m, 10H), 6.93 (d, 2H), 4.34 (s, 2H), 3.87 (m, 2H),3.29 (m, 8H), 2.78 (m, 9H), 2.83 (m, 6H).

EXAMPLE 347

This example was made by substituting(4R)-4-((4-(aminosulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-5-(phenylsulfanyl)pentanamide,prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (d, 1H), 8.31 (d, 1H),7.83 (dd, 1H), 7.73 (d, 2H), 7.51 (m, 2H), 7.24 (m, 12H), 6.90 (d, 2H),4.12 (m, 1H), 3.40 (m, 8H), 3.26 (m, 4H), 2.83 (s, 3H), 2.74 (s, 3H),2.39 (m, 4H), 1.97 (m, 2H).

EXAMPLE 348A

A mixture of tert-butyl(2E,4R)-4-((tert-butoxycarbonyl)amino)-5-(phenylsulfanyl)pent-2-enoate,prepared as described in WO02/24636, (14 g) and tris(triphenylphosphinerhodium chloride (Wilkinson's catalyst) (2 g) in toluene (250 mL) at 45°C. was stirred under hydrogen (balloon) for 48 hours, filtered throughsilica gel and concentrated.

EXAMPLE 348B

EXAMPLE 348A (6.3 g) in dichloromethane at 25° C. was treated withmeta-chloroperbenzoic acid (8.8 g), stirred for 6 hours, poured intoethyl acetate, washed with aqueous sodium carbonate and brine, andconcentrated. The concentrate was flash chromatographed on silica gelwith 50% ethyl acetate/hexanes.

EXAMPLE 348C

This example was made by substituting EXAMPLE 348B for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 348D

EXAMPLE 348C (5.1 g), dimethylamine hydrochloride (2.33 g), EDAC.HCl(8.21 g), DMAP (1.74 g), and TEA (3.97 mL) in dichloromethane (75 mL) at25° C. was stirred for 24 hours, poured into water, and extracted withethyl acetate. The extract was washed with water and brine andconcentrated. The concentrate was flash chromatogrphed on silica gelwith 10% methanol/ethyl acetate.

EXAMPLE 348E

This example was made by substituting EXAMPLE 348D for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 348F

This example was made by substituting EXAMPLE 348E for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 348G

This example was made by substituting for EXAMPLE 348F for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 12.14 (m, 1H), 10.90 (m, 1H),9.82 (m, 1H), 8.50 (d, 1H), 8.12 (d, 1H), 8.05 (m, 1H), 7.90 (dd, 1H),7.80 (d, 2H), 7.45 (m, 12H), 6.93 (d, 2H), 4.35 (s, 2H), 4.22 (m, 1H),3.89 (m, 2H), 3.28 (m, 4H), 2.96 (m, 4H), 2.80 (m, 4H), 2.68 (m, 6H),1.71 (m, 4H).

EXAMPLE 349

A mixture of EXAMPLE 26H (45 mg), 2-chloro-N,N-dimethylacetamide (50mg), and DIEA (0.2 mL) in dioxane(1 mL) at 80° C. was stirred for 18hours and concentrated. The concentrate was flash chromatographed onsilica gel with 5% 7M NH₃ in methanol/dichloromethane. ¹H NMR (500 MHz,DMSO-d₆) δ 12.13 (m, 1H), 11.31 (m, 1H), 9.58 (m, 1H), 8.53 (d, 1H),8.28 (d, 1H), 8.11 (m, 1H), 7.87 (m, 1H), 7.78 (d, 2H), 7.53 (m, 4H),7.24 (m, 10H), 6.93 (d, 2H), 4.35 (s, 2H), 4.23 (m, 1H), 4.21 (s, 2H),3.89 (m, 2H), 3.27 (m, 8H), 2.88 (m, 6H), 2.78 (s, 3H), 2.22 (m, 2H).

EXAMPLE 350

This example was made by substituting tert-butylamine for isopropylaminein EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (m, 1H), 9.58 (m, 1H),8.70 (d, 1H), 8.52 (d, 1H), 7.83 (dd, 1H), 7.77 (d, 2H), 7.67 (s, 1H),7.53 (m, 4H), 7.25 (m, 10H), 6.93 (d, 2H), 4.37 (m, 2H), 3.89 (m, 2H),2.98 (m, 8H), 2.62 (dd, 2H), 1.15 (s, 9H).

EXAMPLE 351

This example was made by substituting diisopropylamine forisopropylamine in EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 12.08 (m, 1H),9.61 (m, 1H), 8.79 (d, 1H), 8.52 (d, 1H), 7.83 (dd, 1H), 7.77 (d, 2H),7.54 (m, 3H), 7.25 (m, 10H), 6.93 (d, 2H), 4.41 (m, 2H), 3.96 (m, 3H),2.98 (m, 8H), 2.84 (m, 2H), 1.14 (m, 12H).

EXAMPLE 352

This example was made by substituting N-methyl-tert-butylamine forisopropylamine in EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 12.05 (m, 1H),9.59 (m, 1H), 8.80 (d, 1H), 8.53 (d, 1H), 7.83 (dd, 1H), 7.77 (d, 2H),7.52 (m, 3H), 7.25 (m, 10H), 6.93 (d, 2H), 4.42 (m, 2H), 3.92 (m, 1H),2.98 (m, 8H), 2.80 (s, 3H), 2.84 (m, 2H), 1.27 (s, 9H).

EXAMPLE 353

This example was made by substituting N-methyl-isopropylamine forisopropylamine in EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 12.07 (m, 1H),9.62 (m, 1H), 8.82 (d, 1H), 8.53 (d, 1H), 7.83 (dd, 1H), 7.77 (d, 2H),7.25 (m, 10H), 6.93 (d, 2H), 4.61 (m, 1H), 4.43 (m, 2H), 4.05 (m, 1H),3.92 (m, 1H), 2.98 (m, 8H), 2.72 (s, 3H), 2.84 (m, 2H), 0.99 (m, 6H).

EXAMPLE 354

This example was made by substituting piperidine for isopropylamine inEXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 12.06 (m, 1H), 9.62 (m, 1H),8.79 (d, 1H), 8.53 (d, 1H), 7.83 (dd, 1H), 7.77 (d, 2H), 7.52 (m, 3H),7.25 (m, 10H), 6.93 (d, 2H), 4.44 (m, 2H), 3.89 (m, 1H), 3.35 (m, 4H),2.99 (m, 8H), 3.00 (dd, 2H), 2.75 (dd, 2H), 1.42 (m, 6H).

EXAMPLE 355A

This example was made by substitutingtert-butyl(5R)-5-((4-(aminosulfonyl)-2-nitrophenyl)amino)-6-(phenylsulfanyl)hexylcarbamate(prepared as described in WO 02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 355B

A mixture of EXAMPLE 355A (100 mg) and TFA (1 mL) in dichloromethane (1mL) at 25° C. were stirred for 2 hours and concentrated. The concentratewas flash chromatographed on silica gel with 5-10% (7M NH₃ inmethanol)/dichloromethane.

EXAMPLE 355C

A mixture of EXAMPLE 355B (50 mg), N,N-dimethylglycine (23 mg), EDAC.HCl(42 mg) and DMAP (27.2 mg) in dichloromethane (2 mL) at 25° C. wasstirred for 18 hours, treated with ethyl acetate, washed with aqueousNaHCO₃, water and brine, and dried (Na₂SO₄), filtered, and concentrated.The concentrate was flash chromatographed on silica gel with 5-10% 7MNH₃ in methanol/dichloromethane. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m,1H), 11.53 (m, 1H), 9.92 (m, 1H), 8.63 (t, 1H), 8.53 (d, 1H), 8.30 (d,1H), 8.16 (m, 1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.52 (m, 3H), 7.22 (m,8H), 6.93 (d, 2H), 4.33 (s, 2H), 4.10 (m, 1H), 3.85 (m, 2H), 3.37 (m,4H), 3.12 (m, 8H), 2.84 (m, 6H), 1.76 (m, 2H), 1.34 (m, 4H).

EXAMPLE 356

This example was made by substituting dimethylamine for isopropylaminein EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (d, 1H), 8.52 (d, 1H),7.83 (dd, 1H), 7.74 (d, 2H), 7.45 (m, 7H), 7.18 (m 6H), 6.90 (d, 2H),4.40 (m, 1H), 3.40 (m, 4H), 3.25 (m, 4H), 2.96 (dd, 2H), 2.89 (s, 3H),2.78 (s, 3H), 2.70 (dd, 2H), 2.45 (m 2H).

EXAMPLE 357

This example was made by substituting thiomorpholine 1,1-dioxide,prepared as described in J. Med. Chem 1994, 37, 913-933, forisopropylamine in EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (d, 1H),8.47 (d, 1H), 7.80 (dd, 1H), 7.73 (d, 2H), 7.32 (m, 13H), 6.83 (d, 2H),3.82 (m, 4H), 3.39 (m, 4H), 3.18 (m, 8H), 3.04 (m, 3H), 2.89 (dd, 2H),2.40 (m, 2H).

EXAMPLE 357

This example was made by substituting 0.5M NH₃ in dioxane forisopropylamine in EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 8.57 (d, 1H),8.46 (d, 1H), 7.79 (dd, 1H), 7.73 (d, 2H), 7.32 (m, 13H), 6.83 (d, 2H),4.33 (m, 2H), 3.39 (m, 2H), 3.33 (m, 2H), 3.18 (m, 5H), 2.60 (m, 4H),2.40 (m, 2H).

EXAMPLE 359

This example was made by substituting cyclopropylamine forisopropylamine in EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (d, 1H),8.48 (d, 1H), 8.11 (d, 1H), 7.80 (dd, 1H), 7.73 (d, 2H), 7.32 (m, 12H),6.83 (d, 2H), 4.32 (m, 2H), 3.39 (m, 2H), 3.34 (m, 2H), 3.20 (m, 5H),2.56 (m, 4H), 2.40 (m 2H), 0.54 (m, 2H), 0.29 (m, 2H).

EXAMPLE 360

This example was made by substituting cyclobutylamine for isopropylaminein EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d, 1H), 8.48 (d, 1H),8.27 (d, 1H), 7.80 (dd, 1H), 7.73 (d, 2H), 7.32 (m, 12H), 6.85 (d, 2H),4.33 (m, 2H), 4.10 (m, 1H), 3.40 (m, 2H), 3.38 (m, 2H), 3.20 (m, 5H),2.57 (m, 4H), 2.40 (m 2H), 2.08 (m, 2H), 1.77 (m, 2H), 1.58 (m, 2H).

EXAMPLE 361

This example was made by substituting 1-methylpiperazine forisopropylamine in EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 12.09 (m, 1H),10.52 (m, 1H), 8.73 (m, 1H), 8.53 (d, 1H), 7.84 (dd, 1H), 7.76 (d, 2H),7.53 (m 4H), 7.24 (m, 10H), 6.93 (d, 2H), 4.37 (m, 3H), 3.96 (m, 4H),3.28 (m, 6H), 3.20 (m, 5H), 2.88 (m, 4H), 2.75 (m 3H), 2.54 (m, 2H).

EXAMPLE 362

This example was made by substituting morpholine for isopropylamine inEXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (d, 1H), 8.50 (d, 1H), 7.81(dd, 1H), 7.73 (d, 2H), 7.32 (m, 12H), 6.86 (d, 2H), 4.39 (m, 2H), 3.44(m, 13H), 3.32 (m, 2H), 2.98 (dd, 2H), 2.77 (dd, 2H), 2.40 (m, 2H).

EXAMPLE 363

This example was made by substituting azetidine for isopropylamine inEXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 8.71 (d, 1H), 8.50 (d, 1H), 7.81(dd, 1H), 7.73 (d, 2H), 7.31 (m, 12H), 6.86 (d, 2H), 4.31 (m, 1H), 4.04(t, 2H), 3.79 (m, 2H), 3.40 (m, 4H), 3.23 (m, 4H), 2.64 (dd, 2H), 2.52(dd, 2H), 2.40 (m, 2H), 2.12 (m, 2H).

EXAMPLE 364

This example was made by substituting 4-(2-aminoethyl)morpholine forisopropylamine in EXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (m, 1H),10.52 (m, 1H), 8.74 (d, 1H), 8.51 (d; 1H), 8.45 (t, 1H), 7.83 (dd, 1H),7.77 (d, 2H), 7.54 (m, 3H), 7.24 (m, 10H), 6.92 (d, 2H), 4.40 (m, 1H),4.35 (m, 2H), 3.89 (m, 4H), 3.72 (m, 4H), 3.39 (m, 6H), 3.20 (m, 4H),3.10 (m, 2H), 2.88 (m, 2H), 2.73 (m, 2H).

EXAMPLE 365

This example was made by substituting methylamine for isopropylamine inEXAMPLE 28. ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (d, 1H), 8.45 (d, 1H), 7.98(m, 1H), 7.78 (dd, 1H), 7.73 (d, 2H), 7.32 (m, 12H), 6.83 (d, 2H), 4.30(m, 1H), 3.39 (s, 2H), 3.29 (m, 2H), 3.18 (m, 4H), 2.61 (m, 4H), 2.53(d, 3H), 2.40 (m, 2H).

EXAMPLE 366

This example was made by substituting 7M NH₃ in methanol forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (d, 1H),8.08 (d, 1H), 7.83 (dd, 1H), 7.72 (d, 2H), 7.31 (m, 12H), 6.93 (m, 1H),6.78 (d, 2H), 4.10 (m, 2H), 3.38 (s, 2H), 3.33 (m, 2H), 3.12 (m, 5H),2.87 (t, 2H), 2.40 (m, 2H), 2.00 (m, 2H).

EXAMPLE 367

This example was made by substituting sodium cyanide for isopropylaminein example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (d, 1H), 8.22 (d, 1H),7.83 (dd, 1H), 7.74 (d, 2H), 7.31 (m, 12H), 7.04 (d, 1H), 6.87 (d, 2H),4.11 (m, 2H), 3.35 (m, 4H), 3.22 (m, 5H), 2.60 (t, 2H), 2.39 (m, 2H),2.09 (m, 2H).

EXAMPLE 368

This example was made by substituting tert-butylamine for isopropylaminein example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m, 1H), 10.94 (m,1H), 8.75 (m, 1H), 8.53 (d, 1H), 8.30 (d, 1H), 8.05 (m, 1H), 7.87 (dd,1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.23 (m, 10H), 6.93 (d, 2H), 4.34 (m,2H), 3.88 (m, 2H), 3.42 (d, 2H), 3.27 (m, 5.H), 2.89 (m, 4H), 2.14 (m,2H), 1.24 (s, 9H).

EXAMPLE 369

This example was made by substituting cyclopropylamine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m,1H), 10.84 (m, 1H), 9.04 (m, 1H), 8.53 (d, 1H), 8.30 (d, 1H), 8.02 (m,1H), 7.86 (dd, 1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.24 (m, 8H), 6.93 (d,2H), 4.35 (m, 3H), 3.88 (m, 2H), 3.27 (m, 5H), 3.09 (m, 2H), 2.87 (m,2H), 2.66 (m, 2H), 2.14 (m, 2H), 0.82 (m, 2H), 0.70 (m, 2H).

EXAMPLE 370

This example was made by substituting cylcobutylamine for isopropylaminein example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m, 1H), 10.88 (m,1H), 9.04 (m, 1H), 8.53 (d, 1H), 8.27 (d, 1H), 8.04 (m, 1H), 7.86 (dd,1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.24 (m, 8H), 6.93 (d, 2H), 4.35 (m,3H), 3.88 (m, 2H), 3.61 (m, 2H), 3.27 (m, 6H), 2.86 (m, 4H), 2.71 (m,1H), 2.11 (m, 4H), 1.76 (m, 2H).

EXAMPLE 138

This example was made by substituting diethylamine for isopropylamine inexample 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m, 1H), 10.99 (m, 1H),10.08 (m, 1H), 8.53 (d, 1H), 8.29 (d, 1H), 8.06 (m, 1H), 7.86 (dd, 1H),7.78 (d, 2H), 7.53 (m, 4H), 7.24 (m, 8H), 6.93 (d, 2H), 4.34 (m, 3H),3.88 (m, 2H), 3.39 (m, 2H), 3.27 (m, 6H), 3.08 (m, 4H), 2.81 (m, 2H),2.15 (m, 2H), 1.17 (m, 6H).

EXAMPLE 372

This example was made by substituting N-methylisopropylamine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m,1H), 10.89 (m, 1H), 9.96 (m, 1H), 8.53 (d, 1H), 8.29 (m, 1H), 8.04 (m,1H), 7.85 (dd, 1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.24 (m, 8H), 6.93 (d,2H), 4.34 (m, 3H), 3.88 (m, 2H), 3.42 (m, 2H), 3.27 (m, 6H), 2.86 (m,2H), 2.60 (m, 3H), 2.15 (m, 2H), 1.19 (m, 6H).

EXAMPLE 373

This example was made by substituting N-methyl-tert-butylamine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (m,1H), 10.84 (m, 1H), 9.70 (m, 1H), 8.53 (d, 1H), 8.30 (t, 1H), 8.03 (m,1H), 7.85 (dd, 1H), 7.78 (d, 2H), 7.52 (m, 4H), 7.23 (m, 8H), 6.93 (d,2H), 4.35 (m, 3H), 3.88 (m, 2H), 3.43 (m, 2H), 3.27 (m, 6H), 2.86 (m,2H), 2.64 (m, 3H), 2.22 (m, 2H), 1.29 (d, 9H).

EXAMPLE 374

This example was made by substituting piperidine for isopropylamine inexample 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (m, 1H), 10.95 (m, 1H),9.97 (m, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 8.04 (m, 1H), 7.85 (dd, 1H),7.78 (d, 2H), 7.54 (m, 4H), 7.23 (m, 8H), 6.93 (d, 2H), 4.35 (m, 2H),4.22 (m, 1H), 3.88 (m, 2H), 3.40 (m, 2H), 3.27 (m, 6H), 3.10 (m, 2H),2.81 (m, 6H), 2.22 (m, 2H), 1.75 (m, 4H), 1.35 (m, 2H).

EXAMPLE 375

This example was made by substituting 4-hydroxypiperidine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (m,1H), 10.85 (m, 1H), 9.98 (m, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 8.04 (m,1H), 7.85 (dd, 1H), 7.78 (d, 2H), 7.54 (m, 4H), 7.24 (m, 8H), 6.93 (d,2H), 4.36 (m, 2H), 4.22 (m, 1H), 3.93 (m, 3H), 3.27 (m, 6H), 3.10 (m,2H), 2.87 (m, 4H), 2.22 (m, 2H), 1.91 (m, 4H), 1.70 (m, 2H).

EXAMPLE 376

This example was made by substituting 1-acetylpiperazine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (m,1H), 10.69 (m, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 7.99 (m, 1H), 7.85 (dd,1H), 7.78 (d, 2H), 7.54 (m, 4H), 7.23 (m, 8H), 6.93 (d, 2H), 4.36 (m,2H), 4.22 (m, 1H), 3.92 (m, 2H), 3.41 (m, 4H), 3.27 (m, 6H), 3.00 (m,2H), 2.85 (m, 6H), 2.22 (m, 2H), 2.02 (s, 3H).

EXAMPLE 377

This example was made by substituting thiomorpholine for isopropylaminein example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (m, 1H), 10.69 (m,1H), 10.55 (m, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 7.99 (m, 1H), 7.85 (dd,1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.25 (m, 8H), 6.93 (d, 2H), 4.36 (m,2H), 4.25 (m, 1H), 3.90 (m, 2H), 3.64 (m, 4H), 3.41 (m, 4H), 3.17 (m,9H), 2.82 (m, 4H), 2.22 (m, 2H).

EXAMPLE 378

This example was made by substituting 4-(2-aminoethyl)morpholine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m,1H), 10.63 (m, 1H), 9.26 (m, 1H), 8.53 (d, 1H), 8.29 (d, 1H), 7.99 (m,1H), 7.86 (dd, 1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.25 (m, 8H), 6.93 (d,2H), 4.36 (m, 2H), 4.25 (m, 1H), 3.90 (m, 2H), 3.77 (m, 2H), 3.41 (m,4H), 3.27 (m, 6H), 3.05 (m, 6H), 2.82 (m, 4H), 2.17 (m, 2H).

EXAMPLE 379A

This example was made by substituting tert-butyl 1-piperazinecarboxylatefor isopropylamine in example 35B.

EXAMPLE 379B

This example was made by substituting EXAMPLE 379A for EXAMPLE 27B inEXAMPLE 29A. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m, 1H), 10.90 (m, 1H),9.50 (m, 1H), 8.53 (d, 1H), 8.30 (d, 1H), 8.04 (m, 1H), 7.84 (dd, 1H),7.78 (d, 2H), 7.53 (m, 4H), 7.22 (m, 8H), 6.93 (d, 2H), 4.36 (m, 2H),4.27 (m, 1H), 3.90 (m, 2H), 3.40 (m, 6H), 3.17 (m, 10H), 2.86 (m, 2H),2.23 (m, 2H).

EXAMPLE 380

This example was made by substituting (S)-3-hydroxypyrrolidine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m,1H), 10.73 (m, 1H), 10.26 (m, 1H), 8.53 (d, 1H), 8.29 (d, 1H), 8.04 (m,1H), 7.85 (m, 1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.24 (m, 8H), 6.93 (d,2H), 4.35 (m, 3H), 3.88 (m, 2H), 3.38 (m, 4H), 3.17 (m, 6H), 3.03 (m,1H), 2.87 (m, 4H), 2.17 (m, 2H), 1.91 (m, 2H).

EXAMPLE 381A

This example was made by substituting3(R)-(tert-butoxycarbonylamino)pyrrolidine for isopropylamine in example35B.

EXAMPLE 381B

This example was made by substituting EXAMPLE 381A for EXAMPLE 27B inEXAMPLE 29A. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m, 1H), 11.09 (m, 1H),10.92 (m, 1H), 8.53 (d, 1H), 8.47 (m, 1H), 8.30 (d, 1H), 8.04 (m, 1H),7.85 (m, 1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.23 (m, 8H), 6.93 (d, 2H),4.35 (m, 3H), 3.88 (m, 2H), 3.40 (m, 4H), 3.27 (m, 6H), 3.08 (m, 1H),2.86 (m, 4H), 2.22 (m, 2H), 2.05 (m, 2H).

EXAMPLE 382

This example was made by substituting 3-hydroxyazetidine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (m,1H), 10.73 (m, 1H), 10.23 (m, 1H), 8.53 (d, 1H), 8.27 (d, 1H), 8.00 (m,1H), 7.85 (dd, 1H), 7.78 (d, 2H), 7.52 (m, 4H), 7.24 (m, 8H), 6.93 (d,2H), 4.35 (m, 2H), 4.26 (m, 3H), 4.04 (m, 1H), 3.88 (m, 2H), 3.71 (m,2H), 3.24 (m, 8H), 2.86 (m, 2H), 1.98 (m, 2H).

EXAMPLE 383

This example was made by substituting 1-methylpiperazine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m,1H), 10.91 (m, 1H), 8.53 (d, 1H), 8.31 (d, 1H), 8.04 (m, 1H), 7.85 (dd,1H), 7.78 (d, 2H), 7.54 (m, 4H), 7.24 (m, 8H), 6.93 (d, 2H), 4.34 (m,2H), 4.26 (m, 1H), 3.88 (m, 2H), 3.40 (m, 6H), 3.27 (m, 8H), 2.86 (m,4H), 2.80 (s, 3H), 2.21 (m, 2H).

EXAMPLE 384

This example was made by substituting thiomorpholine 1,1-dioxide,prepared as described in J. Med. Chem 1994, 37, 913-933, forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.08 (m,1H), 10.97 (m, 1H), 8.53 (d, 1H), 8.31 (d, 1H), 8.04 (m, 1H), 7.86 (dd,1H), 7.77 (d, 2H), 7.53 (m, 4H), 7.23 (m, 8H), 6.93 (d, 2H), 4.35 (m,2H), 4.26 (m, 2H), 3.88 (m, 2H), 3.55 (m, 5H), 3.24 (m, 8H), 2.89 (m,4H), 1.98 (m, 2H).

EXAMPLE 385

This example was made by substituting 3,4-methylenedioxyaniline forisopropylamine in example 35B. ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (m,1H), 11.29 (m, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 8.12 (m, 1H), 7.82 (dd,1H), 7.77 (d, 2H), 7.53 (m, 4H), 7.24 (m, 9H), 6.93 (m, 4H), 6.07 (s,2H), 4.35 (m, 2H), 4.26 (m, 2H), 3.28 (m, 9H), 2.85 (m, 4H), 2.15 (m,2H).

EXAMPLE 386

This example was made by substituting 3,4-methylenedioxybenzylamine forisopropylamine in example 35B. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (m,1H), 11.29 (m, 1H), 9.26 (m, 1H), 8.53 (d, 1H), 8.26 (d, 1H), 8.11 (m,1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.53 (m, 4H), 7.24 (m, 9H), 6.90 (m,4H), 6.02 (s, 2H), 4.34 (m, 3H), 3.98 (m, 2H), 3.87 (m, 2H), 3.61 (m,2H), 3.28 (m, 4H), 2.91 (m, 4H), 2.16 (m, 2H).

EXAMPLE 387

This example was made by substituting 2-aminomethylpyridine forisopropylamine in example 35B. ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (m,1H), 11.57 (m, 1H), 9.46 (m, 3H), 8.53 (d, 1H), 8.26 (d, 1H), 8.11 (m,1H), 7.86 (m, 1H), 7.78 (d, 2H), 7.51 (m, 4H), 7.24 (m, 9H), 6.93 (d,2H), 4.33 (m, 2H), 4.26 (m, 1H), 3.87 (m, 2H), 3.39 (m, 4H), 3.25 (m,4H), 2.84 (m, 4H), 2.22 (m, 2H).

EXAMPLE 388

This example was made by substituting 2-aminoethylpyridine forisopropylamine in example 35B. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (m,1H), 11.36 (m, 1H), 9.29 (m, 3H), 8.62 (d, 1H), 8.53 (d, 1H), 8.28 (d,1H), 8.13 (m, 1H), 7.86 (d, 1H), 7.78 (d, 2H), 7.53 (m, 4H), 7.18 (m,9H), 6.93 (d, 2H), 4.33 (m, 2H), 3.87 (m, 2H), 3.31 (m, 7H), 3.05 (m,4H), 2.84 (m, 4H), 2.18 (m, 2H).

EXAMPLE 389

This example was made by substituting 4-aminomethylpyridine forisopropylamine in example 35B. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (m,1H), 11.30 (m, 1H), 9.85 (m, 2H), 9.17 (m, 1H), 8.76 (d, 1H), 8.53 (d,1H), 8.27 (d, 1H), 8.11 (m, 1H), 7.85 (d, 1H), 7.78 (d, 2H), 7.53 (m,4H), 7.19 (m, 9H), 6.93 (d, 2H), 4.33 (m, 2H), 4.23 (m, 1H), 3.87 (m,2H), 3.29 (m, 6H), 3.05 (m, 2H), 2.84 (m, 4H), 2.23 (m, 2H).

EXAMPLE 390

This example was made by substituting 4-aminomorpholine forisopropylamine in example 35B. ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (m,1H), 11.55 (m, 1H), 9.39 (m, 3H), 8.54 (d, 1H), 8.32 (d, 1H), 8.11 (m,1H), 7.87 (d, 1H), 7.77 (d, 2H), 7.51 (m, 4H), 7.24 (m, 8H), 6.92 (d,2H), 4.33 (m, 2H), 4.23 (m, 1H), 4.00 (m, 1H), 3.87 (m, 2H), 3.31 (m,9H), 3.05 (m, 4H), 2.84 (m, 4H), 2.33 (m, 2H).

EXAMPLE 391

This example was made by substituting N-methyl-4-aminopyridine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m,1H), 10.83 (m, 1H), 8.68 (m, 3H), 8.52 (d, 1H), 8.19 (t, 2H), 8.01 (m,1H), 7.83 (d, 1H), 7.77 (d, 2H), 7.52 (m, 4H), 7.25 (m, 8H), 7.01 (d,1H), 6.93 (d, 2H), 6.74 (m, 2H), 4.33 (m, 2H), 4.24 (m, 2H), 3.87 (m,3H), 3.36 (m 4H), 3.26 (m, 4H), 2.83 (d, 3H), 2.33 (m, 2H).

EXAMPLE 392

This example was made by substituting 3-aminopyridine for isopropylaminein example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (m, 1H), 10.80 (m,1H), 8.72 (m, 3H), 8.52 (d, 1H), 8.22 (d, 2H), 7.99 (m, 1H), 7.83 (d,1H), 7.77 (d, 2H), 7.52 (m, 4H), 7.19 (m, 8H), 7.02 (d, 1H), 6.93 (d,2H), 6.59 (m, 1H), 4.52 (m, 2H), 4.33 (m, 2H), 4.12 (m, 1H), 3.87 (m,2H), 3.36 (m 4H), *3.26 (m, 2H), 2.85 (d, 2H), 2.40 (m, 2H).

EXAMPLE 393

This example was made by substituting 2,6-dimethylpiperidine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.09 (m,1H), 10.62 (m, 1H), 9.74 (m, 1H), 8.64 (m, 1H), 8.50 (d, 1H), 8.30 (d,1H), 7.99 (m, 1H), 7.86 (d, 1H), 7.77 (d, 2H), 7.5 2 (m, 4H), 7.24 (m,8H), 6.93 (d, 2H), 4.36 (m, 2H), 3.88 (m, 2H), 3.31 (m 9H), 2.85 (d,4H), 2.15 (m, 2H), 1.79 (m, 2H), 1.64 (m, 4H), 1.26 (m, 6H).

EXAMPLE 394

This example was made by substituting cis-2,6-dimethylpiperidine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (m,1H), 10.78 (m, 1H), 9.80 (m, 1H), 8.74 (m, 1H), 8.50 (d, 1H), 8.30 (d,1H), 8.01 (m, 1H), 7.86 (d, 1H), 7.77 (d, 2H), 7.52 (m, 4H), 7.24 (m,8H), 6.93 (d, 2H), 4.35 (m, 2H), 3.88 (m, 2H), 3.31 (m 9H), 2.85 (d,4H), 2.15 (m, 2H), 1.79 (m, 2H), 1.64 (m, 4H), 1.26 (m, 6H).

EXAMPLE 395

This example was made by substituting 1-aminopyrrolidine forisopropylamine in example 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.12 (m,1H), 10.86 (m, 1H), 8.73 (m, 1H), 8.54 (d, 1H), 8.32 (d, 1H), 8.02 (m,1H), 7.86 (d, 1H), 7.77 (d, 2H), 7.52 (m, 4H), 7.25 (m, 8H), 6.93 (d,2H), 4.36 (m, 2H), 4.22 (m, 1H), 3.88 (m, 2H), 3.31 (m 10H), 2.85 (d,4H), 2.32 (m, 2H), 2.11 (m, 4H).

EXAMPLE 396A

A mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (2 g),methoxylamine hydrochloride (0.85 g), and potassium acetate (0.98 g) inethanol (40 mL) was stirred at reflux for 18 hours and concentrated. Theconcentrate was treated with ethyl acetate (200 mL), washed with waterand brine, and dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was used without further purification.

EXAMPLE 396B

A mixture of EXAMPLE 396A (2.1 g) and TFA (10 mL) in dichloromethane (10mL) at 25° C. was stirred for 4 hours and concentrated.

EXAMPLE 396C

This example was made by substituting EXAMPLE 396B for isopropylamine inEXAMPLE 35B. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (d, 1H), 7.82 (dd, 1H),7.72 (d, 2H), 7.52 (m, 4H), 7.32 (m, 10H), 6.87 (d, 2H), 4.17 (m, 1H),3.71 (s, 3H), 3.32 (m 10H), 2.73 (m, 2H), 2.40 (m, 6H), 2.25 (m, 4H),1.91 (m, 2H).

EXAMPLE 397

A mixture of EXAMPLE 367 (80 mg), sodium azide (33 mg), and ammoniumchloride (27 mg) in DMF (2 mL) at 110° C. was stirred for 18 hours,treated with ethyl acetate (100 mL), washed with water and brine, dried(Na₂SO₄), filtered, and concentrated. The concentrate was flashchromatographed on silica gel with 3% methanol/dichloromethane. ¹H NMR(300 MHz, DMSO-d₆) δ 12.09 (m, 1H), 10.15 (m, 1H), 8.52 (d, 1H), 8.32(d, 1H), 7.82 (dd, 1H), 7.78 (d, 2H), 7.52 (m, 4H), 7.24 (m, 8H), 6.93(d, 2H), 4.37 (m, 2H), 4.20 (m, 1H), 3.71 (s, 3H), 3.28 (m, 5H), 2.98(t, 2H), 2.83 (m, 2H), 2.23 (m, 2H).

EXAMPLE 398A

This example was made by substituting4-bromo-3-trifluoromethylbenzenesulfonamide for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 398B

A mixture of EXAMPLE 27B (2 g) and diethylamine (5 mL) in THF (20 mL) at25° C. was stirred for 18 hours and concentrated. The concentrate wasflash chromatographed on silica gel with 3% (7M NH₃ inmethanol)/dichloromethane.

EXAMPLE 398C

This example was made by substituting EXAMPLE 398A and EXAMPLE 398B forEXAMPLE 164B and 164A, respectively, in EXAMPLE 164C.

EXAMPLE 398D

This example was made by substituting EXAMPLE 398C for EXAMPLE 27D inEXAMPLE 27E.

EXAMPLE 398E

This example was made by substituting EXAMPLE 398D for EXAMPLE 27E inEXAMPLE 34.

EXAMPLE 398F

This example was made by substituting EXAMPLE 398E for EXAMPLE 34 inEXAMPLE 35A.

EXAMPLE 398G

This example was made by substituting EXAMPLE 398F and diisopropylaminefor EXAMPLE 35A and isopropylamine, respectively, in EXAMPLE 35B. ¹H NMR(500 MHz, DMSO-d₆) δ 11.94 (m, 1H), 11.07 (m, 1H), 9.25 (m, 1H), 8.06(m, 1H), 7.93 (d, 1H), 7.82 (dd, 1H), 7.74 (d, 2H), 7.51 (m, 4H), 7.27(m, 8H), 6.93 (t, 2H), 6.08 (d, 1H), 4.33 (m, 2H), 4.00 (m, 1H), 3.87(m, 2H), 3.55 (m, 4H), 3.28 (m, 4H), 2.90 (m, 4H), 2.17 (m, 2H), 1.22(m, 12H).

EXAMPLE 399

This example was made by substituting EXAMPLE 398F for EXAMPLE 35A inEXAMPLE 35B. ¹H NMR (500 MHz, DMSO-d₆) δ 11.95 (m, 1H), 11.11 (m, 1H),8.74 (m, 1H), 8.06 (m, 1H), 7.94 (d, 1H), 7.91 (s, 1H), 7.81 (dd, 1H),7.74 (d, 2H), 7.51 (m, 4H), 7.26 (m, 6H), 6.96 (d, 1H), 6.91 (d, 2H),5.99 (d, 1H), 4.33 (m, 2H), 4.03 (m, 1H), 3.87 (m, 2H), 3.31 (m, 5H),2.88 (m, 6H), 2.07 (m, 2H), 1.18 (m, 6H).

EXAMPLE 400

This example was made by substituting diethanolamine for isopropylaminein EXAMPLE 35B. ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (d, 1H), 8.30 (m, 1H),8.01 (s, 1H), 7.93 (dd, 1H), 7.82 (d, 2H), 7.41 (m, 11H), 7.10 (d, 1H),6.93 (d, 2H), 4.50 (m, 1H), 4.23 (m, 1H), 3.75 (m, 4H), 3.49 (m, 4H),3.28 (m, 4H), 3.33 (m, 7H), 2.59 (m, 2H), 2.23 (m, 2H).

EXAMPLE 401A

A mixture of 1-bromo-2-(trifluoromethoxy)benzene (5 g) andchlorosulfonic acid (30 mL) at 85° C. were stirred for 18 hours, treatedwith crushed ice, and extracted with ethyl acetate. The extract waswashed with water and brine and dried (Na₂SO₄), filtered, andconcentrated. The concentrate in IPA (200 mL) at 0° C. was treated with38% ammonium hydroxide (50 mL), stirred for 18 hours and concentrated.The concentrate was treated with ethyl acetate (200 mL) and water. Theextract was washed with water and brine and dried (Na₂SO₄), filtered,and concentrated.

EXAMPLE 401B

This example was made by substituting EXAMPLE 401A for EXAMPLE4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 401C

This example was made by substituting EXAMPLE 401B for EXAMPLE 164B inEXAMPLE 164C. ¹H NMR (500 MHz, DMSO-d₆) δ 11.92 (m, 1H), 11.12 (m, 1H),10.18 (m, 1H), 7.92 (d, 1H), 7.56 (d, 2H), 7.31 (m, 4H), 7.08 (m, 6H),6.73 (d, 2H), 5.86 (d, 1H), 4.15 (m, 2H), 3.68 (m, 2H), 3.59 (m, 1H),3.09 (m, 4H), 2.91 (m, 4H), 2.66 (m, 2H), 2.31 (m, 6H), 1.95 (m, 2H).

EXAMPLE 402

This example was made by substituting EXAMPLE 398F andmethylisopropylamine for EXAMPLE 35A and isopropylamine, respectively,in EXAMPLE 35B. ¹H NMR (500 MHz, DMSO-d₆) δ 11.96 (m, 1H), 11.40 (m,1H), 10.39 (m, 1H), 8.14 (m, 1H), 7.95 (d, 1H), 7.81 (d, 1H), 7.76 (d,2H), 7.53 (m, 4H), 7.28 (m, 7H), 6.93 (m, 3H), 6.03 (m, 1H), 4.33 (m,2H), 4.02 (m, 1H), 3.87 (m, 2H), 3.32 (m, 6H), 3.04 (m, 2H), 2.86 (m,2H), 2.57 (m, 3H), 2.19 (m, 2H), 1.19 (m, 6H).

EXAMPLE 403

This example was made by substituting EXAMPLE 398F and diethylamine forEXAMPLE 35A and isopropylamine, respectively, in EXAMPLE 35B. ¹H NMR(500 MHz, DMSO-d₆) δ 11.96 (m, 1H), 11.28 (m, 1H), 10.30 (m, 1H), 8.11(m, 1H), 7.94 (s, 1H), 7.81 (d, 1H), 7.76 (d, 2H), 7.53 (m, 4H), 7.28(m, 7H), 6.93 (m, 3H), 6.06 (m, 1H), 4.33 (m, 2H), 4.02 (m, 1H), 3.87(m, 2H), 3.24 (m, 4H), 3.14 (m, 2H), 3.04 (m, 4H), 2.88 (m, 4H), 2.13(m, 2H), 1.17 (m, 6H).

EXAMPLE 404

This example was made by substituting 2,5-dimethylpyrrolidine forisopropylamine, in EXAMPLE 35B. ¹H NMR (500 MHz, DMSO-d₆) δ 12.10 (m,1H), 11.41 (m, 1H), 10.55 (m, 1H), 9.88 (m, 1H), 8.54 (s, 1H), 8.31 (d,1H), 8.14 (m, 1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.53 (m, 4H), 7.24 (m,8H), 6.93 (d, 2H), 4.33 (m, 2H), 3.88 (m, 2H), 3.26 (m, 7H), 2.83 (d,2H), 2.16 (m, 4H), 1.65 (m, 2H), 1.36 (m, 6H).

EXAMPLE 405

This example was made by substituting EXAMPLE 398F and 7M NH₃ inmethanol for EXAMPLE 35A and isopropylamine, respectively, in EXAMPLE35B. ¹H NMR (500 MHz, DMSO-d₆) δ 7.92 (s, 1H), 7.87 (d, 1H), 7.72 (d,2H), 7.51 (dd, 1H), 7.29 (m, 7H), 6.77 (m, 2H), 6.69 (m, 1H), 4.40 (m,1H), 3.87 (m, 2H), 3.38 (m, 4H), 3.12 (m, 4H), 2.84 (t, 2H), 2.40 (m,2H), 1.99 (m, 2H).

EXAMPLE 406A

This example was made by substituting4-bromo-2-trifluoromethylbenzenesulfonamide for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 406B

This example was made by substituting EXAMPLE 406A for EXAMPLE 164B inEXAMPLE 164C. ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, 1H), 7.79 (d, 2H),7.48 (dd, 1H), 7.26 (m, 11H), 6.78 (m, 3H), 6.56 (m, 2H), 3.64 (m, 2H),3.12 (m, 5H), 3.06 (m, 2H), 2.80 (m, 4H), 2.36 (m, 6H), 2.01 (m, 2H),1.74 (m, 2H).

EXAMPLE 407A

This example was made by substituting 4-bromo-3-fluorobenzenesulfonamidefor4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 407B

This example was made by substituting EXAMPLE 407A for EXAMPLE 164B inEXAMPLE 164C. ¹H NMR (500 MHz, DMSO-d₆) δ 7.69 (d, 2H), 7.48 (dd, 1H),7.42 (d, 1H), 7.25 (m, 12H), 6.77 (m, 2H), 6.44 (t, 1H), 5.90 (d, 1H),3.63 (m, 2H), 3.10 (m, 9H), 2.79 (m, 4H), 2.36 (m, 6H), 1.98 (m, 1H),1.87 (m, 1H).

EXAMPLE 847398A

This example was made by substituting4-bromo-2-trifluoromethoxybenzenesulfonamide for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 847398B

This example was made by substituting EXAMPLE 847398A for EXAMPLE 164Bin EXAMPLE 164C. ¹H NMR (500 MHz, DMSO-d₆) δ 7.73 (d, 2H), 7.62 (d, 1H),7.51 (d, 1H), 7.31 (m, 12H), 6.81 (m, 2H), 6.39 (m, 2H), 3.61 (m, 2H),3.39 (m, 2H), 3.17 (m, 6H), 3.09 (m, 4H), 2.79 (m, 1H), 2.40 (m, 6H),1.98 (m, 1H), 1.87 (m, 1H).

EXAMPLE 409A

This example was made by substituting4-bromo-2,5-difluorobenzenesulfonamide for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 409B

This example was made by substituting EXAMPLE 409A for EXAMPLE 164B inEXAMPLE 164C. ¹H NMR (500 MHz, DMSO-d₆) δ 7.73 (d, 2H), 7.51 (d, 1H),7.31 (m, 10H), 6.80 (d, 2H), 6.20 (m, 2H), 6.10 (m, 2H), 3.59 (m, 1H),3.39 (m, 4H), 3.14 (m, 6H), 2.94 (m, 2H), 2.85 (m, 2H), 2.40 (m, 6H),2.01 (m, 1H), 1.90 (m, 1H).

EXAMPLE 410A

This example was made by substituting 4-bromo-3-methylbenzenesulfonamidefor4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 410B

This example was made by substituting EXAMPLE 410A for EXAMPLE 164B inEXAMPLE 164C. ¹H NMR (500 MHz, DMSO-d₆) δ 7.72 (d, 2H), 7.51 (d, 1H),7.29 (m, 10H), 6.83 (d, 2H), 6.34 (d, 2H), 5.75 (s, 2H), 5.52 (d, 1H),3.72 (m, 1H), 3.39 (m, 2H), 3.15 (m, 8H), 2.64 (m, 2H), 2.54 (m, 2H),2.40 (m, 6H), 2.05 (s, 3H), 1.98 (m 1H), 1.87 (m, 1H).

EXAMPLE 411

This example was made by substituting EXAMPLE 307C and EXAMPLE 29D forEXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ 8.44 (s, 1H),8.14 (m, 1H), 7.81 (m, 1H), 7.71 (d, 2H), 7.25 (m, 7H), 6.94 (d, 1H),6.77 (d, 2H), 4.11 (m, 1H), 3.58 (m, 2H), 3.19 (m, 6H), 2.76 (s, 2H),2.22 (m, 8H), 1.66 (m, 4H), 1.19 (m, 12H), 0.89 (m, 4H).

EXAMPLE 412

This example was made by substituting(2R,5R)-(−)-trans-2,5-dimethylpyrrolidine, prepared as described in J.Org. Chem. 1999, 64, 1979-1985, for isopropylamine in EXAMPLE 35B. ¹HNMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.17 (m, 1H), 7.84 (dd, 1H), 7.72(d, 2H), 7.51 (d, 1H), 7.27 (m, 8H), 6.99 (d, 1H), 6.79 (d, 2H), 4.14(m, 2H), 3.88 (m, 2H), 3.74 (m, 1H), 3.38 (s, 2H), 3.28 (m, 6H), 2.87(m, 2H), 2.40 (m, 6H), 2.09 (m, 4H), 1.24 (m, 4H).

EXAMPLE 413

This example was made by substituting(2S,5S)-(+)-trans-2,5-dimethylpyrrolidine, prepared as described in J.Org. Chem. 1999, 64, 1979-1985, for isopropylamine in EXAMPLE 35B. ¹HNMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.17 (m, 1H), 7.84 (dd, 1H), 7.72(d, 2H), 7.51 (d, 1H), 7.27 (m, 8H), 6.94 (m, 1H), 6.79 (d, 2H), 4.11(m, 2H), 3.88 (m, 2H), 3.74 (m, 1H), 3.38 (s, 2H), 3.27 (m, 6H), 2.87(m, 2H), 2.40 (m, 6H), 2.09 (m, 4H), 1.24 (m, 4H).

EXAMPLE 414

This example was made by substituting(2S,5R)-cis-2,5-dimethylpyrrolidine, prepared as described in J. Org.Chem. 1999, 64, 1979-1985, for isopropylamine in EXAMPLE 35B. ¹H NMR(500 MHz, DMSO-d₆) δ 8.46 (d, 1H), 8.16 (m, 1H), 7.83 (dd, 1H), 7.72 (d,2H), 7.51 (d, 1H), 7.27 (m, 8H), 6.97 (m, 1H), 6.80 (d, 2H), 4.12 (m,2H), 3.49 (m, 1H), 3.39 (s, 2H), 3.28 (m, 8H), 2.40 (m, 6H), 2.12 (m,4H), 1.57 (m, 2H), 1.21 (m, 4H).

EXAMPLE 415A

A mixture of 4-bromo-3-(trifluoromethyl)benzenesulfonyl chloride (0.46g), concentrated sulfuric acid (6 mL), and 90% nitric acid (3 mL) at110° C. were stirred for 18 hours, poured into ice water and extractedwith ethyl acetate. The extract was washed with water and brine, dried(Na₂SO₄), filtered, and concentrated.

EXAMPLE 415B

EXAMPLE 415A (0.5 g) in IPA (25 mL) and THF (25 mL) at −78° C. wastreated with 38% ammonium hydroxide (10 mL), stirred for 3 hours,acidified with 12M HCl, and concentrated. The concentrate was treatedwith ethyl acetate and water. The extract was washed with water andbrine and dried (Na₂SO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 25% ethyl acetate/hexane.

EXAMPLE 415C

A mixture of EXAMPLE 415B (0.235 g), EXAMPLE 164A (0.224 g) and DIEA (1mL) in dimethylacetamide (10 mL) at 50° C. was stirred for 18 hours,treated with ethyl acetate, washed with aqueous NaHCO₃, water, andbrine, and dried (MgSO₄), filtered, and concentrated. The concentratewas flash chromatographed on silica gel with 50% ethylacetate/NH₃-saturated dichloromethane.

EXAMPLE 415D

This example was made by substituting EXAMPLE 415C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.41 (d, 1H), 8.20 (d, 1H),7.83 (dd, 1H), 7.75 (d, 2H), 7.51 (dd, 1H), 7.37 (m, 8H), 7.06 (d, 2H),6.79 (d, 2H), 6.50 (m, 1H), 3.39 (s, 2H), 3.29 (m 1H), 3.05 (m, 7H),2.63 (m, 4H), 2.40 (m, 6H), 2.07 (m, 2H).

EXAMPLE 416

This example was made by substituting EXAMPLE 415C and EXAMPLE 307C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ8.31 (d, 1H), 8.10 (d, 1H), 7.65 (d, 2H), 7.27 (d, 2H), 7.04 (m, 8H),6.68 (d, 2H), 6.44 (m, 1H), 3.04 (m, 4H), 2.82 (m, 1H), 2.69 (m, 2H),2.41 (m, 6H), 2.20 (m, 4H), 2.08 (m, 4H), 1.98 (m, 2H), 1.56 (m, 4H).

EXAMPLE 417

This example was made by substituting EXAMPLE 415C and EXAMPLE 318C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ8.18 (d, 1H), 7.98 (d, 1H), 7.52 (d, 2H), 7.15 (d, 2H), 6.94 (m, 8H),6.56 (d, 2H), 6.42 (m, 1H), 2.90 (m, 4H), 2.69 (m, 1H), 2.56 (m, 2H),2.29 (m, 6H), 2.19 (m, 4H), 2.10 (m, 4H), 1.82 (m, 1H), 1.74 (m, 1H),1.56 (m, 4H), 1.48 (m, 2H), 1.32 (m, 4H).

EXAMPLE 418A

3-Fluoro-4-nitrobenzenesulfonyl chloride (1 g) in IPA (50 mL) at −15° C.was treated with 38% NH₄OH (10 mL), stirred for 18 hours andconcentrated. The concentrate was partitioned between ethyl acetate andwater. The water layer was extracted with ethyl acetate. The extract waswashed with water and brine and dried (Na₂SO₄), filtered, andconcentrated.

EXAMPLE 418B

This example was made by substituting EXAMPLE 418A and EXAMPLE 164A for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 21C, respectively, inEXAMPLE 21D.

EXAMPLE 418C

This example was made by substituting EXAMPLE 418B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, 1H), 7.95 (d, 2H),7.60 (s, 1H), 7.51 (dd, 1H), 7.37 (m, 4H), 7.30 (d, 4H), 7.24 (dd, 1H),7.14 (t, 2H), 7.08 (t, 1H), 7.02 (dd, 1H), 6.79 (d, 2H), 4.13 (m, 1H),3.49 (dd, 1H), 3.39 (d, 2H), 3.36 (dd, 1H), 3.13 (m, 4H), 3.04 (m, 2H),2.63 (m, 4H), 2.40 (m, 6H), 2.10 (m, 2H).

EXAMPLE 419A

This example was made by substituting4-bromo-3,5-difluorobenzenesulfonyl chloride for3-fluoro-4-nitrobenzenesulfonyl chloride in EXAMPLE 418A.

EXAMPLE 419B

This example was made by substituting EXAMPLE 419A for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D.

EXAMPLE 419C

This example was made by substituting EXAMPLE 419B for EXAMPLE 164B inEXAMPLE 164C. ¹H NMR (500 MHz, DMSO-d₆) δ 12.10 (m, 1H), 11.43 (m, 1H),10.48 (m, 1H), 8.55 (m, 1H), 8.14 (m, 2H), 7.77 (m, 2H), 7.33 (m, 12H),6.93 (m, 2H), 6.03 (d, 2H), 4.34 (m 1H), 3.88 (m, 2H), 3.36 (m, 4H),3.13 (m, 2H), 2.84 (m, 2H), 2.70 (m, 6H), 2.08 (m, 2H).

EXAMPLE 420A

A mixture of 2-chloro-3-nitrobenzoic acid (5 g) and chlorosulfonic acid(30 mL) at 150° C. was stirred for 72 hours, treated with ice, andextracted ethyl acetate. The extract was washed with water and brine,dried (Na₂SO₄), filtered, and concentrated. The concentrate in 1:1IPA/THF (200 mL) at −78° C. was treated with 38% ammonium hydroxide (30mL), stirred for 2 hours, acidified with 12M HCl, and concentrated. Theconcentrate was treated with water and ethyl acetate. The extract waswashed with water and brine and dried (Na₂SO₄), filtered, andconcentrated.

EXAMPLE 420B

EXAMPLE 420A (4.5 g) in methanol (300 mL) was treated with concentratedsulfuric acid (3 mL), stirred at reflux for 18 hours, and concentrated.The concentrate was treated with water and ethyl acetate. The extractwas washed with water and brine and dried (Na₂SO₄), filtered, andconcentrated. The concentrate was flash chromatographed on silica gelwith 20% ethyl acetate/hexane.

EXAMPLE 420C

This example was made by substituting EXAMPLE 420B and EXAMPLE 164A for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 21C, respectively, inEXAMPLE 21D.

EXAMPLE 420D

This example was made by substituting EXAMPLE 420C and EXAMPLE 307C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ8.34 (s, 1H), 8.28 (d, 1H), 7.72 (d, 2H), 7.36 (d, 2H), 7.13 (m, 7H),6.76 (d, 2H), 3.80 (s, 3H), 3.10 (m, 4H), 2.75 (m, 2H), 2.27 (m, 4H),2.18 (m, 6H), 1.99 (m, 2H), 1.88 (m, 2H), 1.65 (m, 4H).

EXAMPLE 421

This example was made by substituting EXAMPLE 420C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.20 (d, 1H),7.66 (d, 2H), 7.43 (d, 2H), 7.16 (m, 11H), 6.71 (d, 2H), 3.74 (s, 3H),3.05 (m, 6H), 2.82 (m, 2H), 2.49 (m, 6H), 2.32 (m, 4H), 1.95 (m, 2H),1.85 (m, 2H).

EXAMPLE 422

EXAMPLE 421 (60 mg) in THF (1 mL), methanol (1 mL), and water (1 mL) wastreated with lithium hydroxide monohydrate (10 mg), stirred at 25° C.for 18 hours, and concentrated. The concentrate was purified by highpressure liquid chromatography on a Waters Symmetry C₈ column (25 mm×100mm, 7 μm particle size) with 10-100% acetonitrile/0.1% aqueous TFA over8 minutes at a flow rate of 40 mL/minute. ¹H NMR (500 MHz, DMSO-d₆) δ9.55 (m, 1H), 9.13 (m, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 7.79 (d, 2H),7.72 (m, 1H), 7.52 (m, 4H), 7.49 (m, 2H), 7.33 (m, 2H), 7.09 (m, 4H),6.99 (m, 2H), 6.93 (d, 2H), 4.21 (m, 1H), 3.17 (m, 6H), 2.93 (m, 2H),2.79 (m, 6H), 2.12 (m, 2H), 2.05 (m, 2H).

EXAMPLE 423

This example was made by substituting EXAMPLE 420D for EXAMPLE 421 inEXAMPLE 422. ¹H NMR (500 MHz, DMSO-d₆) δ 9.57 (m, 1H), 9.21 (m, 1H),8.47 (s, 1H), 8.33 (s, 1H), 7.80 (d, 2H), 7.40 (m, 4H), 7.15 (d, 2H),7.09 (m, 4H), 7.01 (m, 2H), 6.95 (d, 2H), 3.17 (m, 6H), 2.79 (m, 6H),2.26 (m, 4H), 2.21 (m, 4H), 2.14 (m, 2H), 2.03 (m, 2H), 1.70 (m, 4H).

EXAMPLE 424

EXAMPLE 420D (100 mg) in 7M NH₃ in methanol at 70° C. was stirred for 48hours in a sealed vial, and concentrated. The concentrate was purifiedby high pressure liquid chromatography on a Waters Symmetry C₈ column(25 mm×100 mm, 7 μm particle size) with 10-100% acetonitrile/0.1%aqueous TFA over 8 minutes at a flow rate of 40 mL/minute. ¹H NMR (500MHz, DMSO-d₆) δ 9.46 (m, 1H), 8.52 (m, 1H), 8.45 (d, 1H), 7.99 (s, 1H),7.87 (s, 1H), 7.79 (d, 2H), 7.41 (m, 4H), 7.16 (d, 2H), 7.13 (m, 4H),6.96 (d, 2H), 3.90 (m, 1H), 3.59 (m, 2H), 3.35 (m, 4H), 3.27 (m, 4H),3.17 (m, 6H), 2.77 (m, 6H), 2.26 (m, 4H), 2.21 (m, 4H), 2.10 (m, 2H),1.71 (m, 4H).

EXAMPLE 425

This example was made by substituting EXAMPLE 421 for EXAMPLE 420D inEXAMPLE 424. ¹H NMR (500 MHz, DMSO-d₆) δ 9.42 (m, 1H), 8.52 (m, 1H),8.46 (d, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.78 (d, 2H), 7.53 (m, 4H),7.41 (d, 2H), 7.34 (m, 1H), 7.14 (m, 4H), 6.94 (d, 2H), 3.91 (m, 1H),3.36 (m, 4H), 3.28 (m, 4H), 3.16 (m, 6H), 2.77 (m, 6H), 2.11 (m, 2H).

EXAMPLE 426A

2-Fluoro-3-(trifluoromethyl)benzoic acid (5 g) in concentrated sulfuricacid (50 mL) at 0° C. was treated with urea nitrate, prepared asdescribed in Textbook of Practical Organic Chemistry; 1971, page 442, (5g), stirred for 30 minutes and at 25° C. for 12 hours, poured ontocrushed ice and extracted with ethyl acetate. The extract was washedwith water and brine, dried (Na₂SO₄), filtered, and concentrated. Theconcentrate in methanol (300 mL) and concentrated sulfuric acid (3 mL)was refluxed for 18 hours and concentrated. The concentrate was treatedwith water and ethyl acetate, and the organic layer was washed withwater and brine, and dried (Na₂SO₄), filtered, and concentrated.

EXAMPLE 426B

EXAMPLE 426A (6 g) and 10% palladium on carbon (0.6 g) in ethyl acetate(200 mL) at 25° C. were shaken under H₂ (60 psi) for 2 hours, filteredand concentrated.

EXAMPLE 426C

This example was made by substituting EXAMPLE 426B for EXAMPLE 848090Ain EXAMPLE 848090B.

EXAMPLE 426D

This example was made by substituting EXAMPLE 426C and EXAMPLE 164A for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 21C, respectively, inEXAMPLE 21D.

EXAMPLE 426E

This example was made by substituting EXAMPLE 426D and EXAMPLE 307C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ8.39 (d, 1H), 8.16 (d, 1H), 7.72 (d, 2H), 7.36 (d, 2H), 7.30 (m, 1H),7.20 (d, 2H), 7.12 (m, 4H), 6.77 (d, 2H), 3.81 (s, 3H), 3.62 (m, 1H),3.12 (m, 8H), 2.95 (m, 2H), 2.77 (m, 2H), 2.61 (m, 6H), 2.28 (m, 4H),2.18 (m, 4H), 2.10 (m, 2H), 1.91 (m, 2H), 1.66 (m, 4H).

EXAMPLE 427

This example was made by substituting EXAMPLE 426D and EXAMPLE 312D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ8.39 (d, 1H), 8.15 (d, 1H), 7.72 (d, 2H), 7.40 (d, 2H), 7.30 (m, 1H),7.20 (m, 4H), 7.12 (m, 2H), 6.77 (d, 2H), 4.16 (s, 2H), 3.81 (s, 3H),3.79 (t, 2H), 3.62 (m, 1H), 3.12 (m, 8H), 2.95 (m, 2H), 2.88 (m, 4H),2.60 (m, 6H), 2.30 (m, 4H), 2.05 (m, 2H), 1.91 (m, 2H).

EXAMPLE 428

This example was made by substituting EXAMPLE 426D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, 1H), 8.16 (d, 1H),7.73 (d, 2H), 7.50 (d, 2H), 7.47 (m, 4H), 7.24 (m, 6H), 6.79 (d, 2H),3.81 (s, 3H), 3.61 (m, 1H), 3.38 (s, 2H), 3.12 (m, 8H), 2.95 (m, 2H),2.61 (m, 6H), 2.40 (m, 4H), 2.10 (m, 2H), 1.91 (m, 2H).

EXAMPLE 429A

This example was made by substituting Fmoc-D-Glu(O-tert-butyl)-OH forFmoc-D-Asp(O-tert-butyl)-OH in EXAMPLE 27A.

EXAMPLE 429B

This example was made by substituting EXAMPLE 429A for EXAMPLE 27A inEXAMPLE 27B.

EXAMPLE 429C

This example was made by substituting EXAMPLE 429B for EXAMPLE 27B inEXAMPLE 29A.

EXAMPLE 429D

This example was made by substituting EXAMPLE 429C and(2S,5R)-cis-2,5-dimethylpyrrolidine, prepared as described in J. Org.Chem. 1999, 64, 1979-1985, for EXAMPLE 29A and diisopropylamine,respectively, in EXAMPLE 29B.

EXAMPLE 429E

This example was made by substituting EXAMPLE 429D for EXAMPLE 27B inEXAMPLE 398B.

EXAMPLE 429F

This example was made by substituting EXAMPLE 429E for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 429G

This example was made by substituting EXAMPLE 429F for EXAMPLE 21C inEXAMPLE 21D.

EXAMPLE 429H

This example was made by substituting EXAMPLE 429G and EXAMPLE 307C for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ12.11 (m, 1H), 10.17 (m, 1H), 9.01 (m, 1H), 8.53 (d, 1H), 8.32 (d, 1H),7.87 (dd, 1H), 7.79 (d, 2H), 7.41 (d, 2H), 7.18 (m, 6H), 6.96 (d, 2H),4.18 (m, 1H), 3.90 (m, 2H), 3.60 (m, 2H), 3.09 (m, 2H), 2.78 (m, 2H),2.26 (m, 4H), 2.09 (m, 2H), 1.68 (m, 8H), 1.28 (d, 6H).

EXAMPLE 430

This example was made by substituting EXAMPLE 429G and EXAMPLE 312D for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamideand EXAMPLE 2C, respectively, in EXAMPLE 2D. ¹H NMR (300 MHz, DMSO-d₆) δ12.11 (m, 1H), 10.54 (m, 1H), 9.00 (m, 1H), 8.53 (d, 1H), 8.32 (d, 1H),7.88 (dd, 1H), 7.78 (d, 2H), 7.45 (d, 2H), 7.18 (m, 6H), 6.96 (d, 2H),4.38 (s, 2H), 4.18 (m, 1H), 3.84 (t, 2H), 3.66 (m, 2H), 3.09 (m, 2H),2.75 (m, 2H), 2.46 (m, 4H), 2.09 (m, 2H), 1.68 (m, 8H), 1.28 (d, 6H).

EXAMPLE 431

This example was made by substituting 2-tert-butoxycarbonylaminobenzoylchloride for 2-bromobenzoyl chloride in EXAMPLE 106B. ¹H NMR (500 MHz,DMSO-d₆) δ 9.48 (s, 1H), 9.28 (brs, 1H), 8.55 (d, 1H), 8.28 (d, 1H),7.88 (dd, 1H), 7.77 (d, 2H), 7.24 (d, 2H), 7.16 (dd, 2H), 7.12 (d, 1H),6.96 (d, 2H), 6.63 (d, 1H), 6.58 (s, 1H), 6.50 (d, 1H), 4.18 (m, 1H),3.40 (m, 4H), 3.35 (m, 2H), 3.20-3.08 (m, 4H), 2.73 (s, 6H), 2.54 (s,2H), 2.14 (m, 2H), 1.48 (s, 9H).

EXAMPLE 432

This example was made by substituting 2-dimethylaminobenzoyl chloridefor 2-bromobenzoyl chloride in EXAMPLE 106B. ¹H NMR (500 MHz, DMSO-d₆) δ9.26 (br s, 1H), 8.55 (d, 1H), 8.28 (d, 1H), 7.87 (dd, 1H), 7.77 (d,2H), 7.23 (d, 2H), 7.15 (dd, 2H), 7.11 (d, 1H), 6.96 (d, 2H), 6.79 (d,1H), 6.69 (s, 1H), 6.65 (d, 1H), 4.17 (m, 1H), 3.40 (m, 4H), 3.35 (m,2H), 3.15 (m, 4H), 2.91 (s, 6H), 2.74 (s, 6H), 2.54 (s, 2H), 2.14 (m,2H).

EXAMPLE 433A

This example was made by substituting(2S,4R)-3-((benzyloxy)carbonyl)-4-methyl-2-phenyl-1,3-oxazolidin-5-one,(prepared as described in Helv. Chim. Acta 1991, for(2R,4S)-3-((benzyloxy)carbonyl)-4-methyl-2-phenyl-1,3-oxazolidin-5-onein EXAMPLE 25A.

EXAMPLE 433B

This example was made by substituting EXAMPLE 433A for EXAMPLE 25A inEXAMPLE 21B.

EXAMPLE 433C

This example was made by substituting EXAMPLE 433B for EXAMPLE 25B inEXAMPLE 21C.

EXAMPLE 433D

This example was made by substituting EXAMPLE 433C for EXAMPLE 18A inEXAMPLE 18B.

EXAMPLE 433E

This example was made by substituting EXAMPLE 433D for EXAMPLE 25D inEXAMPLE 21E.

EXAMPLE 433F

This example was made by substituting EXAMPLE 433E for EXAMPLE 25E inEXAMPLE 21F.

EXAMPLE 433G

This example was made by substituting EXAMPLE 433F for EXAMPLE 18B inEXAMPLE 18C.

EXAMPLE 433H

This example was made by substituting EXAMPLE 433G for EXAMPLE 25G inEXAMPLE 25H.

EXAMPLE 433I

This example was made by substituting EXAMPLE 433H for EXAMPLE 1C inEXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (d, 1H), 8.31 (s, 1H), 7.92(dd, 1H), 7.81 (d, 2H), 7.60 (d, 1H), 7.47 (m, 4H), 7.42 (m, 3H), 7.32(m, 4H), 7.16 (dd, 2H), 7.08 (dd, 1H), 6.86 (d, 2H), 4.25 (m, 1H), 3.77(d, 2H), 3.45 (d, 1H), 3.21 (m, 4H), 2.95 (m, 1H), 2.67 (s, 6H), 2.54(m, 1H), 2.45 (m, 4H), 2.27 (m, 1H), 1.59 (s, 3H).

EXAMPLE 434

This example was made by substituting EXAMPLE 25H for EXAMPLE 1C inEXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 10.20 (br s, 1H), 8.48 (d, 1H),8.26 (s, 1H), 7.87 (dd, 1H), 7.78 (d, 2H), 7.56 (d, 1H), 7.42 (m, 4H),7.38 (m, 3H), 7.29 (d, 1H), 7.25 (m, 3H), 7.05 (dd, 2H), 6.97 (dd, 1H),6.83 (d, 2H), 3.74 (m, 1H), 3.45 (s, 2H), 3.39 (d, 1H), 3.28 (m, 1H),3.20 (m, 4H), 3.16 (m, 1H), 2.97 (m, 1H), 2.67 (s, 6H), 2.54 (m, 1H),2.40 (m, 4H), 2.25 (m, 1H), 1.54 (s, 3H).

EXAMPLE 435A

2-fluorobenzonitrile (0.325 mL) in isoindoline/NMP (1 mL/2 mL) at 180°C. was stirred for 10 minutes in a microwave reactor, poured intodiethyl ether (50 mL) and washed with 1M HCl and brine. The solution wasdried (Na₂SO₄), filtered, and concentrated.

EXAMPLE 435B

EXAMPLE 435A (200 mg) in toluene (5 mL) at 25° C. was treated with 1MDIBAL in dichloromethane (1.1 mL), stirred for 30 minutes, treated withmethanol (3 mL), poured into 1M HCl (50 mL), and extracted with ethylacetate. The extract was washed with brine and dried (Na₂SO₄), filtered,and concentrated. The concentrate was flash chromatographed on silicagel with 10% ethyl acetate/hexanes.

EXAMPLE 435C

This example was made by substituting EXAMPLE 435B for EXAMPLE 130D inEXAMPLE 130E. ¹H NMR (500 MHz, DMSO-d₆) δ 10.05 (br s, 1H), 8.45 (d,1H), 8.21 (d, 1H), 7.81 (dd, 1H), 7.73 (d, 2H), 7.34 (m, 4H), 7.23 (m,4H), 7.18 (m, 2H), 7.07 (m, 1H), 6.89 (m, 2H), 6.81 (d, 2H), 4.62 (ABquartet, 4H), 4.09 (m, 1H), 3.62 (s, 1H), 3.34 (m, 2H), 3.28 (m, 1H),3.20 (m, 2H), 2.91 (dd, 2H), 2.84 (m, 1H), 2.67 (s, 6H), 2.55 (m, 4H),2.09 (m, 1H), 2.02 (m, 1H), 1.71 (m, 1H).

EXAMPLE 436A

This example was made by substituting cyclohexylamine for isoindoline inEXAMPLE 435A.

EXAMPLE 436B

This example was made by substituting EXAMPLE 436A for EXAMPLE 435A inEXAMPLE 435B.

EXAMPLE 436C

This example was made by substituting EXAMPLE 436B for2-(methylsulfanyl)benzaldehyde in EXAMPLE 128E. ¹H NMR (400 MHz,DMSO-d₆) δ 9.70 (br s, 1H), 8.52 (d, 1H), 8.22 (d, 1H), 7.84 (dd, 1H),7.76 (d, 2H), 7.26 (d, 2H), 7.19 (m, 2H), 7.11 (m, 2H), 6.97 (dd, 1H),6.89 (d, 2H), 6.58 (d, 1H), 6.49 (m, 1H), 4.19 (m, 1H), 3.51 (m, 1H),3.38 (d, 2H), 3.34 (m, 5H), 3.11 (m, 4H), 2.70 (s, 6H), 2.47 (m, 3H),2.17 (m, 2H), 1.88 (m, 2H), 1.62 (m, 2H), 1.53 (m, 1H), 1.37 (m, 2H),1.22 (m, 4H).

EXAMPLE 437A

This example was made by substituting isopropylamine for isoindoline inEXAMPLE 435A.

EXAMPLE 437B

This example was made by substituting EXAMPLE 437A for EXAMPLE 435A inEXAMPLE 435B.

EXAMPLE 437C

This example was made by substituting EXAMPLE 437B for2-(methylsulfanyl)benzaldehyde in EXAMPLE 128E. ¹H NMR (400 MHz,DMSO-d₆) δ 9.82 (br s, 1H), 8.52 (d, 1H), 8.22 (d, 1H), 7.84 (dd, 1H),7.78 (d, 2H), 7.25 (d, 2H), 7.18 (m, 2H), 7.13 (m, 2H), 6.99 (m, 1H),6.92 (d, 2H), 6.60 (d, 1H), 6.51 (dd, 1H), 4.21 (m, 1H), 3.49 (m, 3H),3.39 (d, 2H), 3.31 (m, 5H), 3.11 (m, 4H), 3.08 (d, 2H), 2.71 (s, 6H),2.51 (m, 1H), 2.16 (m, 2H), 1.14 (d, 6H).

EXAMPLE 438A

This example was made by substituting benzylamine for isoindoline inEXAMPLE 435A.

EXAMPLE 438B

This example was made by substituting EXAMPLE 438A for EXAMPLE 435A inEXAMPLE 435B.

EXAMPLE 438C

This example was made by substituting EXAMPLE 438B for2-(methylsulfanyl)benzaldehyde in EXAMPLE 128E. ¹H NMR (400 MHz,DMSO-d₆) δ 10.18 (br s, 1H), 8.52 (d, 1H), 8.25 (d, 1H), 7.84 (dd, 1H),7.78 (d, 2H), 7.37 (d, 2H), 7.29 (dd, 2H), 7.24 (m, 2H), 7.19 (m, 2H),7.12 (m, 3H), 7.07 (m, 1H), 6.95 (d, 2H), 6.56 (dd, 1H), 6.52 (d, 1H),4.35 (s, 2H), 4.25 (m, 1H), 3.39 (d, 2H), 3.35 (m, 4H), 3.18 (m, 1H),3.05 (m, 8H), 2.68 (s, 6H), 2.51 (m, 1H), 2.19 (m, 2H).

EXAMPLE 439A

This example was made by substituting piperidine for isoindoline inEXAMPLE 435A.

EXAMPLE 439B

This example was made by substituting EXAMPLE 439A for EXAMPLE 435A inEXAMPLE 435B.

EXAMPLE 439C

This example was made by substituting EXAMPLE 439B for2-(methylsulfanyl)benzaldehyde in EXAMPLE 128E. ¹H NMR (400 MHz,DMSO-d₆) δ 8.49 (d, 1H), 8.19 (m, 1H), 7.82 (dd, 1H), 7.75 (d, 2H), 7.41(m, 1H), 7.35 (m, 1H), 7.30 (d, 2H), 7.22 (m, 3H), 7.15 (m, 1H), 7.02(m, 2H), 6.87 (d, 1H), 4.12 (m, 1H), 3.60 (m, 2H), 3.42 (m, 1H), 3.37(d, 2H), 3.31 (m, 5H), 3.22 (m, 2H), 3.08 (m, 2H), 2.82 (m, 4H), 2.69(s, 6H), 2.59 (m, 2H), 2.10 (m, 2H), 1.65 (m, 4H), 1.51 (m, 2H), 1.21(m, 4H).

EXAMPLE 440

This example was made by substituting4-cyclohexylamino-3-nitro-benzenesulfonamide, prepared as described inWO02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.90 (brs, 1H), 8.61 (d,1H), 8.60 (dd, 1H), 7.94 (dd, 1H), 7.74 (d, 2H), 7.59 (d, 1H), 7.41 (dd,2H), 7.38 (m, 4H), 7.25 (d, 1H), 7.22 (d, 1H), 6.89 (d, 2H), 3.58 (m,2H), 3.25 (m, 3H), 2.47 (m, 4H), 1.85 (d, 2H), 1.69 (m, 3H), 1.61 (m,2H), 1.19 (m, 4H), 0.99 (m, 2H).

EXAMPLE 441

This example was made by substituting4-cyclohexylmethylamino-3-nitrobenzenesulfonamide, prepared as describedin WO02/24636, for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 11.90 (br s, 1H), 8.70 (d,1H), 8.36 (dd, 1H), 7.99 (dd, 1H), 7.78 (d, 2H), 7.50 (d, 1H), 7.45 (dd,2H), 7.42 (m, 4H), 7.35 (d, 1H), 7.32 (d, 1H), 6.94 (d, 2H), 3.76 (m,2H), 3.69 (m, 2H), 3.38 (m, 1H), 2.58 (m, 4H), 1.99 (d, 2H), 1.74 (m,3H), 1.62 (m, 2H), 1.45 (m, 6H), 1.29 (m, 2H).

EXAMPLE 442

This example was prepared by substituting EXAMPLE 90C and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (br s,1H), 8.54 (d, 1H), 8.38 (d, 1H), 7.83 (dd, 1H), 7.79 (d, 2H), 7.41 (dd,2H), 7.35 (m, 2H), 7.28 (m, 6H), 7.17 (m, 4H), 6.80 (d, 2H), 4.19 (m,1H), 3.62 (m, 4H), 3.39 (m, 2H), 3.30 (m, 2H), 3.02 (s, 3H), 2.90 (s,2H), 2.85 (dd, 2H), 2.65 (m, 6H), 2.08 (m, 1H), 1.98 (m, 1H), 1.47 (d,2H), 1.18 (m, 2H).

EXAMPLE 443

This example was prepared by substituting EXAMPLE 90C and3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide, preparedas described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (br s,1H), 8.75 (dd, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.79 (d, 2H), 7.41 (dd,2H), 7.36 (m, 3H), 7.28 (m, 6H), 7.17 (m, 3H), 6.80 (d, 2H), 3.66 (m,2H), 3.39 (m, 2H), 3.29 (m, 2H), 3.02 (s, 3H), 2.90 (s, 2H), 2.86 (dd,2H), 1.45 (m, 2H), 1.18 (m, 2H).

EXAMPLE 444A

4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (5 g) in THF (100mL) was treated with saturated NH₄OH at 0° C., stirred for 30 minutesand concentrated. The concentrate in ethyl acetate was washed with waterand brine, and dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 30% ethylacetate in hexanes.

EXAMPLE 444B

A mixture of EXAMPLE 444A (1.5 g) and 2-(phenylsulfanyl)ethanamine (1.06g) in DMSO (17 mL) was treated with TEA (0.97 mL), heated at 145° C. for18 hours, cooled to 25° C., poured into ethyl acetate, washed withwater, brine, dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was flash chromatographed on silica gel with 50% ethylacetate/hexanes.

EXAMPLE 444C

This example was made by substituting EXAMPLE 444B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, 1H), 7.77 (d, 1H),7.73 (dd, 2H), 7.51 (d, 1H), 7.49 (s, 4H), 7.40 (dd, 2H), 7.35 (m, 4H),7.21 (m, 2H), 6.78 (d, 2H), 6.70 (d, 1H), 3.41 (m, 2H), 3.39 (s, 1H),3.16 (m, 2H), 3.13 (m, 4H), 2.50 (s, 1H), 2.40 (m, 4H).

EXAMPLE 445A

This example was made by substituting EXAMPLE 444A for4-fluoro-3-nitrobenzenesulfonamide, prepared as described in WO02/24636,in EXAMPLE 20D.

EXAMPLE 445B

This example was made by substituting EXAMPLE 445A for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 445C

This example was made by substituting EXAMPLE 445B for4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamidein EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 10.90 (br s, 1H), 7.94 (d,1H), 7.79 (d, 1H), 7.74 (d, 2H), 7.53 (d, 1H), 7.47 (s, 4H), 7.38 (m,2H), 7.32 (m, 2H), 7.26 (m, 3H), 7.19 (m, 1H), 6.87 (d, 3H), 3.99 (m,1H), 3.42 (s, 2H), 3.29 (m, 2H), 3.17 (m, 4H), 3.02 (m, 4H), 2.40 (m,4H), 2.16 (m, 2H), 1.89 (m, 4H), 1.28 (m, 2H).

EXAMPLE 446A

4-chloronicotinic acid (5 g) in 1:1 methanol/ethyl acetate (200 mL) wastreated with 2M trimethylsilyldiazomethane (25 mL) and concentrated.

EXAMPLE 446B

A mixture of EXAMPLE 446A (4.88 g), 4-chlorobenzeneboronic acid (5.15g), KF (5.45 g), Pd₂(dba)₃ (260 mg), and tri-tert-butylphosphine in THF(80 mL) at 25° C. was stirred for 3 days, filtered and concentrated. Theconcentrate was flash chromatographed on silica gel with 20% ethylacetate/hexanes.

EXAMPLE 446C

EXAMPLE 446B (3.4 g) in THF (50 mL) at 0° C. was treated with 1M LiAlH₄in THF (14 mL), stirred at 25° C. for 1 hour, quenched with water (5 mL)and 1M NaOH (20 mL), filtered, and concentrated. The concentrate wasflash chromatographed on silica gel with ethyl acetate.

EXAMPLE 446D

EXAMPLE 446C (530 mg) in acetonitrile (15 mL) at 0° C. was treated withpyridine (0.315 mL) and dibromotriphenylphosphorane (1.32 g), stirred at25° C. for 1 hour, and poured into saturated Na₂CO₃ (100 mL) and ethylacetate. The extract was washed with brine and dried (Na₂SO₄), filtered,and concentrated. The concentrate was flash chromatographed on silicagel with 1:1 ethyl acetate/hexanes.

EXAMPLE 446E

This example was made by substituting EXAMPLE 446D for 2-bromobenzylbromide in EXAMPLE 2A.

EXAMPLE 446F

This example was made by substituting EXAMPLE 446E for EXAMPLE 1B inEXAMPLE 1C.

EXAMPLE 446G

This example was made by substituting EXAMPLE 446F for EXAMPLE 1C inEXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.55 (d, 1H), 8.52(d, 1H), 8.23 (d, 1H), 7.85 (dd, 1H), 7.74 (d, 2H), 7.58 (d, 2H), 7.54(d, 2H), 7.31 (d, 1H), 7.26 (d, 1H), 7.17 (dd, 2H), 7.13 (d, 1H), 7.12(m, 1H), 6.88 (d, 2H), 4.19 (m, 1H), 3.47 (s, 2H), 3.32 (m, 4H), 3.11(m, 4H), 2.71 (s, 6H), 2.42 (m, 4H), 2.16 (m, 2H).

EXAMPLE 447

This example was made by substituting EXAMPLE 446F and4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-nitrobenzenesulfonamide,prepared as described in WO 02/24636, for EXAMPLE 2C and4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene-sulfonamide,respectively, in EXAMPLE 2D. ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (s, 1H),8.56 (d, 1H), 8.52 (d, 1H), 8.34 (d, 1H), 7.83 (dd, 1H), 7.74 (d, 2H),7.58 (d, 2H), 7.54 (d, 2H), 7.31 (d, 1H), 7.27 (d, 1H), 7.19 (dd, 2H),7.13 (d, 1H), 7.11 (m, 1H), 6.88 (d, 2H), 4.19 (m, 1H), 3.63 (s, 4H),3.22 (s, 4H), 3.08 (m, 4H), 2.75-2.55 (m, 6H), 2.42 (m, 4H), 2.10 (m,1H), 1.98 (m, 1H).

EXAMPLE 448A

This example was made by substituting 2,6-difluorobenzotrifluoride for1-fluorobenzotrifluoride in EXAMPLE 18D.

EXAMPLE 448B

This example was made by substituting EXAMPLE 448A for EXAMPLE 18D inEXAMPLE 18E.

EXAMPLE 448C

This example was made by substituting EXAMPLE 448B for EXAMPLE 18E inEXAMPLE 18F.

EXAMPLE 448D

This example was made by substituting EXAMPLE 448C for EXAMPLE 1C inEXAMPLE 1D. ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, 2H), 7.76 (dd, 1H),7.64 (d, 1H), 7.54 (d, 2H), 7.51 (d, 2H), 7.44 (m, 2H), 7.40 (d, 2H),7.35 (dd, 2H), 7.31 (d, 1H), 7.25 (dd, 1H), 6.93 (d, 2H), 6.74 (d, 1H),4.02 (m, 1H), 3.55 (m, 4H), 3.35 (m, 2H), 3.18 (m, 2H), 3.06 (m, 2H),2.74 (s, 6H), 2.52 (m, 4H), 2.21 (m, 2H).

EXAMPLE 449A

A solution of piperazine-1-carboxylic acid tert-butyl ester (5.51 g) and2-bromobenzyl bromide (7.776 g) in acetonitrile (60 mL) at 0° C. wastreated with DIEA (7.73 mL), warmed to room temperature andconcentrated. The concentrate was partitioned between ethyl acetate andsaturated sodium bicarbonate. The extract was dried (MgSO₄), filteredand concentrated.

EXAMPLE 449B

A solution of EXAMPLE 449A (5.82 g) and 4-chlorophenylboronic acid(3.089 g) in dimethoxyethane (80 mL) was treated with CsF (7.476 g) andbis(triphenylphosphine)palladium dichloride (1.228 g), stirred at refluxfor 18 hours, cooled and partitioned between ethyl acetate, andsaturated sodium bicarbonate. The extract was washed with brine anddried (MgSO₄), filtered and concentrated. The concentrate was purifiedby flash chromatography on silica gel.

EXAMPLE 449C

A solution of EXAMPLE 449B (4.2 g) in dioxane (30 mL) was treated with4M HCl in dioxane (81 mL), stirred at room temperature for 18 hours andconcentrated.

EXAMPLE 449D

A solution of EXAMPLE 449C (3.852 g) and 2,4-difluorobenzonitrile (2.231g) in acetonitrile (150 mL) was treated with potassium carbonate (5.168g), stirred at reflux for 24 hours, filtered and concentrated. Theconcentrate was purified by chromatography on silica gel with 0-40%ethyl acetate/hexanes.

EXAMPLE 449E

A solution of EXAMPLE 449D (1.438 g) and hydrazine (2.2 mL) in1-methyl-2-pyrrolidinone (1 mL) was heated at 150° C. for 40 minutes ina microwave reactor, concentrated and suspended in THF. The suspensionwas treated with aqueous ammonium hydroxide, filtered and dried.

EXAMPLE 449F

A solution of EXAMPLE 449E (2.0 g) in dioxane (24 mL) was treated withphthalic anhydride (779 mg) and N,N-dimethylaminopyridine (29 mg),stirred at reflux and concentrated. The concentrate was purified bychromatography on silica gel.

EXAMPLE 449G

A solution of EXAMPLE 449F (1.22 g) in dichloromethane (11 mL) wastreated with2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(772 μL) and iodomethane (139 μL), stirred at room temperature for 30minutes and concentrated. The concentrate was purified by chromatographyon silica gel with 0-10% ethyl acetate/dichloromethane.

EXAMPLE 449H

A solution of EXAMPLE 449G (937 mg) in 1:1 dichloromethane/methanol (10mL) was treated with hydrazine (105 μL), stirred at reflux for 18 hoursand concentrated. The concentrate was partitioned betweendichloromethane and aqueous ammonium hydroxide, and the extract wasdried (MgSO₄), filtered and concentrated. The concentrate was purifiedby chromatography on silica gel with 20%-60% acetonitrile/(1-7M ammoniain methanol)/dichloromethane.

EXAMPLE 449I

A solution of EXAMPLE 449H (558 mg) in dichloromethane (7 mL) wastreated with diisopropylethylamine (0.898 mL),4-chloro-3-nitrobenzenesulfonyl chloride (728 mg) andN,N-dimethylaminopyridine (32 mg), stirred at room temperature for 30minutes and partitioned between saturated ammonium chloride and ethylacetate. The extract was washed with brine and dried (MgSO₄), filteredand concentrated. The concentrate was purified by chromatography onsilica gel with 0-80% ethyl acetate/hexanes.

EXAMPLE 449J

A solution of AlCl₃ (0.80 g) in diethyl ether (30 mL) at roomtemperature was treated with LAH (0.68 g). After the addition,(phenylsulfanyl)acetonitrile (0.60 g) in diethyl ether (5 mL) was added,and the mixture was stirred for 4 hours, treated with aqueous 2N NaOHand solid NaOH until clear with a white precipitate and extracted withdiethyl ether. The extract was dried (Na₂SO₄), filtered andconcentrated.

EXAMPLE 449K

A solution of EXAMPLE 449I (117 mg) EXAMPLE 449K (62 mg) in1-methyl-2-pyrrolidinone (0.5 mL) was treated with diisopropylethylamine(117 μL) and heated at 80° C. for 3 hours and concentrated.

EXAMPLE 449L

A solution of the EXAMPLE 449K from the previous step in 1:1THF/methanol (1 mL) was treated with 1M LiOH (1.34 mL), heated at 80° C.for 18 hours and concentrated. The concentrate was partitioned betweenethyl acetate and saturated ammonium chloride and the extract was dried(MgSO₄), filtered and concentrated. The concentrate was purified bychromatography on silica gel with 0-10% 7M ammonia inmethanol/dichloromethane. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (t, 1H), 8.46(d, 1H), 7.77 (br, 1H), 7.72 (d, 1H), 7.52 (dd, 2H), 7.37 (m, 8H), 7.24(m, 4H), 6.89 (d, 1H), 6.61 (d, 1H), 6.48 (s, 1H), 3.83 (s, 3H), 3.49(q, 2H), 3.44 (br, 2H), 3.22 (br, 4H), 3.16 (t, 2H), 2.55 (br, 4H).

EXAMPLE 450A

This example was made by substituting1,1-dimethyl-2-phenylsulfanylethylamine, prepared as described incommonly-owned PCT/US01/29432, published as WO 02/024636, for EXAMPLE449J in EXAMPLE 449K.

EXAMPLE 450B

This example was made by substituting EXAMPLE 450A for EXAMPLE 449K inEXAMPLE 449L. ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 8.39 (d, 1H), 7.77(br, 1H), 7.73 (d, 1H), 7.52 (br, 1H), 7.43 (dd, 1H), 7.38 (m, 6H), 7.25(m, 3H), 7.04 (m, 3H), 6.89 (d, 1H), 6.81 (d, 1H), 6.48 (s, 1H), 3.83(s, 3H), 3.44 (br, 2H), 3.31 (s, 2H), 3.22 (br, 4H), 2.55 (br, 4H), 1.56(s, 6H).

EXAMPLE 451A

This example was made by substituting(R)-N¹,N¹-dimethyl-4-phenylsulfanylbutane-1,3-diamine, prepared asdescribed in commonly-owned U.S. patent application Ser. No. 10/988,388,for EXAMPLE 824469J in EXAMPLE 449K.

EXAMPLE 451B

This example was made by substituting EXAMPLE 451A for EXAMPLE 449K inEXAMPLE 449L. ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, 1H), 8.44 (d, 1H), 7.73(d, 1H), 7.52 (m, 1H), 7.41 (dd, 1H), 7.35 (m, 5H), 7.27 (m, 4H), 7.18(m, 3H), 6.90 (dd, 1H), 6.54 (d, 1H), 6.48 (d, 1H), .3.92 (m, 1H), 3.83(s, 1H), 3.44 (s, 2H), 3.21 (m, 4H), 3.09 (d, 2H), 2.54 (m, 4H), 2.47(m, 1H), 2.30 (m, 1H), 2.21 (s, 6H), 2.03 (m, 1H), 1.82 (m, 1H).

EXAMPLE 452A

This example was made by substituting(R)-3-morpholin-4-yl-1-phenylsulfanylmethylpropylamine, prepared asdescribed in commonly-owned U.S. patent application Ser. No. 10/988,388,for EXAMPLE 824469J in EXAMPLE 449K.

EXAMPLE 452B

This example was made by substituting EXAMPLE 452A for EXAMPLE 449K inEXAMPLE 449L. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (m, 2H), 7.73 (d, 1H), 7.54(br, 1H), 7.44 (dd, 1H), 7.36 (m, 6H), 7.26 (m, 4H), 7.19 (m, 2H), 6.90(d, 1H), 6.60 (d, 1H), 6.48 (s, 1H), 3.97 (m, 1H), 3.83 (s, 3H), 3.64(br, 4H), 3.46 (br, 2H), 3.38 (t, 4H), 3.23 (br, 4H), 3.09 (d, 2H), 2.56(br, 4H), 2.43 (m, 2H), 2.09 (m, 1H), 1.77 (m, 1H).

EXAMPLE 453A

This example was made by substituting trityl chloride for iodomethane inEXAMPLE 449G.

EXAMPLE 453B

This example was made by substituting EXAMPLE 453A for EXAMPLE 449G inEXAMPLE 449H.

EXAMPLE 453C

This example was made by substituting EXAMPLE 453B for EXAMPLE 449H inEXAMPLE 449I.

EXAMPLE 453D

This example was made by substituting EXAMPLE 453C for EXAMPLE 449I inEXAMPLE 449K.

EXAMPLE 453E

This example was made by substituting EXAMPLE 453D for EXAMPLE 449K inEXAMPLE 449L.

EXAMPLE 453F

A solution of EXAMPLE 453E in dichloromethane (1.8 mL) was treated withtriethylsilane (0.1 mL) and trifluoroacetic acid (0.1 mL), stirred atroom temperature for 10 minutes and concentrated. The concentrate waspurified by flash chromatography on silica gel with 0-10% 7M ammonia inmethanol/dichloromethane. ¹H NMR (500 MHz, CDCl₃) δ 9.83 (br, 1H), 8.41(m, 2H), 7.78 (d, 1H), 7.54 (br, 1H), 7.47 (dd, 1H), 7.34 (m, 7H), 7.24(m, 6H), 6.88 (d, 1H), 6.55 (s, 1H), 6.48 (d, 1H), 3.47 (br, 2H), 3.38(q, 2H), 3.18 (br, 4H), 3.09 (t, 2H), 2.54 (br, 4H).

EXAMPLE 454A

This example was made by substituting(R)-N¹,N¹-dimethyl-4-phenylsulfanyl-butane-1,3-diamine, prepared asdescribed in commonly-owned U.S. patent application Ser. No. 10/988,338,and EXAMPLE 453C for EXAMPLE 449J and EXAMPLE 449I, respectively inEXAMPLE 449K.

EXAMPLE 454B

This example was made by substituting EXAMPLE 454A for EXAMPLE 449K inEXAMPLE 449L.

EXAMPLE 454C

This example was made by substituting EXAMPLE 454B for EXAMPLE 453E inEXAMPLE 453F. ¹H NMR (500 MHz, CDCl₃) δ 9.92 (br, 1H), 8.79 (br, 1H),8.41 (d, 1H), 7.76 (d, 1H), 7.51 (d, 1H), 7.36 (m, 7H), 7.25 (m, 4H),7.14 (m, 3H), 6.90 (m, 1H), 6.60 (s, 1H), 6.46 (d, 1H), 3.88 (br, 1H),3.42 (s, 2H), 3.17 (br, 4H), 3.06 (d, 2H), 2.52 (br, 5H), 2.42 (br, 1H),2.28 (s, 6H), 2.03 (m, 1H), 1.86 (m, 1H).

EXAMPLE 455A

This example was made by substituting EXAMPLE 453C and(R)-3-morpholin-4-yl-1-phenylsulfanylmethylpropylamine, prepared asdescribed in commonly-owned U.S. patent application Ser. No. 10/988,388,for EXAMPLE 449I and EXAMPLE 449J, respectively in EXAMPLE 449K.

EXAMPLE 455B

This example was made by substituting EXAMPLE 455A for EXAMPLE 449K inEXAMPLE 449K.

EXAMPLE 455C

This example was made by substituting EXAMPLE 455B for EXAMPLE 453E inEXAMPLE 453F. ¹H NMR (500 MHz, CDCl₃) δ 9.76 (br, 1H), 8.41 (m, 2H),7.81 (d, 1H), 7.53 (d, 1H), 7.35 (m, 7H), 7.26 (m, 4H), 7.13 (m, 3H),6.92 (d, 1H), 6.60 (s, 1H), 6.51 (d, 1H), 3.89 (m, 1H), 3.62 (br, 4H),3.45 (br, 2H), 3.20 (br, 4H), 3.05 (m, 2H), 2.54 (br, 4H), 2.41 (br,4H), 2.32 (br, 2H), 2.07 (m, 1H), 1.75 (m, 1H); MS (ESI) m/z 865.2 (M−H)

EXAMPLE 456A

A solution of acetone oxime (273 mg) and potassium tert-butoxide (442mg) in DMF (10 mL) was stirred at room temperature for 30 minutes,followed by addition of EXAMPLE 449D (1 g) in DMF (10 mL). The mixturewas stirred at room temperature for 18 hours, quenched with saturatedNaHCO₃ solution and extracted with ethyl acetate. The extract was washedwith brine and dried (Na₂SO₄), filtered and and concentrated. Theconcentrate was suspended in 1:1 ethanol/5% HCl (40 mL), stirred atreflux for 2 hours, cooled and concentrated. The concentrate waspurified by flash chromatography on silica gel with 0-15% 7M ammonia inmethanol/dichloromethane.

EXAMPLE 456B

A solution of EXAMPLE 456A (775 mg) in THF (10 mL) was added to asuspension of KH (740 mg) in THF (5 mL) at 0° C. and the mixture waswarmed to room temperature, stirred at room temperature for 30 minutes,cooled to −78° C., treated with 4-chloro-3-nitrobenzenesulfonyl chloride(474 mg) in THF (10 mL), stirred at for 30 minutes, warmed to roomtemperature and poured into saturated ammonium chloride at 0° C.,adjusted to pH 8 with saturated ammonium chloride and extracted withethyl acetate. The extract was dried (MgSO₄), filtered and concentrated.The concentrate was purified by flash chromatography on silica gel with0-15% 7M ammonia in methanol/dichloromethane.

EXAMPLE 456C

A solution of EXAMPLE 456B in dichloromethane (10 mL) was treated with1-chloro-4-chloromethoxy-benzene (125 mg,) and DIEA (335 μL), stirred atreflux for 10 hours and concentrated. The concentrate was purified byflash chromatography on silica gel.

EXAMPLE 456D

A mixture of EXAMPLE 456C (70 mg), 2-phenylsulfanylethylamine (26 mg),diisopropylethylamine (70 μL) and 15 beads of 4A molecular sieves in NMP(1 mL) was stirred at 100° C. for 1 hour, cooled and concentrated. Theconcentrate was purified by flash chromatography on silica gel with30-40% ethyl acetate/hexanes.

EXAMPLE 456E

A solution of EXAMPLE 456D (50 mg) in 1:1 THF/2M HCl (2 mL) was stirredat 60° C. for 2 days, cooled and concentrated. The concentrate waspurified by flash chromatography on silica gel with 1-4%methanol/dichloromethane. ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (t, 1H), 8.54(d, 1H), 7.84 (dd, 1H), 7.64 (d, 1H), 7.51 (d, 1H), 7.47 (m, 4H), 7.38(m, 4H), 7.23 (m, 3H), 7.14 (m, 2H), 7.00 (dd, 9.04 Hz, 1H), 6.87 (d,1H), 4.33 (s, 1H), 3.63 (m, 2H), 3.42 (m, 4H), 3.23 (m, 4H), 2.42 (s,4H).

EXAMPLE 457A

A solution of EXAMPLE 456B in dichloromethane (10 mL) was treated with1-chloro-4-chloromethoxybenzene (125 mg) and diisopropylethylamine (335μL), stirred at reflux for 10 hours and concentrated. The concentratewas purified by flash chromatography on silica gel with 0-100% ethylacetate/hexanes.

EXAMPLE 457B

This example was made by substituting EXAMPLE 457A and(R)-3-morpholin-4-yl-1-phenylsulfanylmethylpropylamine for EXAMPLE 456Cand 2-phenylsulfanyl-ethylamine, respectively, in EXAMPLE 456D.

EXAMPLE 457C

This example was made by substituting EXAMPLE 457B for EXAMPLE 456D inEXAMPLE 456E. ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (d, 1H), 8.38 (d, 1H),7.75 (dd, 1H), 7.59 (d, 1H), 7.47 (m, 51H), 7.37 (m, 2H), 7.24 (m, 3H),7.10 (m, 4H), 6.98 (d, 1H), 6.85 (s, 1H), 5.76 (s, 2H), 4.36 (t, 2H),4.13 (bs, 1H), 3.50 (bs, 4H), 3.38 (m, 4H), 3.21 (bs, 4H), 2.40 (s, 4H),1.92 (m, 1H), 1.77 (m, 1H), 1.43 (m, 4H).

EXAMPLE 458A

This example was made by substituting 4,4-dimethylpiperidine for EXAMPLE449C in EXAMPLE 449D.

EXAMPLE 458B

This example was made by substituting EXAMPLE 458A for EXAMPLE 449D inEXAMPLE 456A.

EXAMPLE 458C

This example was made by substituting EXAMPLE 458B for EXAMPLE 456A inEXAMPLE 456B.

EXAMPLE 458D

This example was prepared by substituting EXAMPLE 458C for EXAMPLE 456Bin EXAMPLE 456C.

EXAMPLE 458E

This example was prepared by substituting EXAMPLE 458D for EXAMPLE 456Cin EXAMPLE 456D.

EXAMPLE 458F

This example was prepared by substituting EXAMPLE 458E for EXAMPLE 456Din EXAMPLE 456E. ¹H NMR (500 MHz, DMSO-d₆) δ 11.59 (bs, 1H), 9.63 (s,1H), 8.72 (t, 1H), 8.55 (d, 1H),7.84 (dd, 1H), 7.64 (d, 1H), 7.33 (m,2H), 7.18 (m, 4H), 7.03 (dd, 1H), 6.88 (d, 1H), 6.76 (m, 1H), 3.64 (m,2H), 3.26 (m, 4H), 1.75 (m, 1H), 1.52 (m, 1H), 1.39 (m, 4H), 0.94 (s,6H).

EXAMPLE 459A

This example was prepared by substituting EXAMPLE 458C for EXAMPLE 456Bin EXAMPLE 456C.

EXAMPLE 459B

This example was made by substituting EXAMPLE 459A and(R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamine for EXAMPLE 456Cand 2-phenylsulfanyl-ethylamine, respectively, in EXAMPLE 456D.

EXAMPLE 459C

This example was prepared by substituting EXAMPLE 459B for EXAMPLE 456Din EXAMPLE 456E. ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (d, 1H), 8.34 (d, 1H),7.77 (m, 1H), 7.61 (d, 1H), 7.21 (d, 2H), 7.10 (m, 4H), 6.99 (d, 1H),6.86 (s, 1H), 4.38 (m, 6H), 4.13 (m, 5H), 3.64 (m, 4H), 3.28 (m, 2H),1.95 (m, 2H), 1.39 (m, 4H), 0.94 (s, 6H).

EXAMPLE 460A

A solution of 1-Boc-piperazine (5.44 g) and β-phenylcinnamaldehyde (6.39g) in 1:1 dichloromethane/methanol (100 mL) was treated with sodiumtriacetoxyborohydride (8.66 g), stirred at room temperature for 18 hoursand concentrated. The concentrate was partitioned betweendichloromethane and saturated sodium bicarbonate, and the extract waswashed with brine and dried (MgSO₄), filtered and concentrated.

EXAMPLE 460B

A solution of EXAMPLE 460A (11 g) in dichloromethane (50 mL) at roomtemperature was treated with 4M HCl in dioxane (50 mL), stirred for 6hours and concentrated. The concentrate was partitioned betweendichloromethane and aqueous sodium carbonate, and the extract was dried(MgSO₄), filtered and concentrated.

EXAMPLE 460C

This example was made by substituting EXAMPLE 460B for EXAMPLE 449C inEXAMPLE 449D.

EXAMPLE 460D

This example was made by substituting EXAMPLE 460C for EXAMPLE 449D inEXAMPLE 456A.

EXAMPLE 460E

This example was made by substituting EXAMPLE 460D for EXAMPLE 456A inEXAMPLE 456B.

EXAMPLE 460F

This example was prepared by substituting EXAMPLE 460E for EXAMPLE 456Bin EXAMPLE 456C.

EXAMPLE 460G

This example was made by substituting EXAMPLE 460F and(R)-3-morpholin-4-yl-1-phenylsulfanylmethylpropylamine for EXAMPLE 456Cand 2-phenylsulfanylethylamine, respectively, in EXAMPLE 456D.

EXAMPLE 460H

This example was prepared by substituting EXAMPLE 460G for EXAMPLE 456Din EXAMPLE 456E. ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (d, 1H), 8.34 (d, 1H),7.74 (dd, 1H), 7.56 (d, 1H), 7.41 (t, 2H), 7.28 (m, 8H), 7.11 (m, 5H),7.03 (d, 1H), 6.95 (d, 1H), 6.84 (s, 1H), 6.19 (t, 1H), 4.33 (t, 2H),4.11 (m, 1H), 3.47 (m, 4H), 3.10 (m, 4H), 2.46 (s, 2H), 2.37 (m, 4H),2.25 (m, 2H), 1.96 (m, 1H), 1.81 (m, 1H), 1.42 (m, 4H).

EXAMPLE 461A

This example was prepared by substituting EXAMPLE 460E for EXAMPLE 456Bin EXAMPLE 456C.

EXAMPLE 461B

This example was prepared by substituting EXAMPLE 461A for EXAMPLE 456Cin EXAMPLE 456D.

EXAMPLE 461C

This example was prepared by substituting EXAMPLE 461B for EXAMPLE 456Din EXAMPLE 456E. ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (t, 1H), 8.51 (d, 1H),7.82 (dd, 1H), 7.59 (d, 1H), 7.42 (t, 2H), 7.32 (m, 5H), 7.23 (m, 5H),7.12 (m, 4H), 6.98 (dd, 1H), 6.86 (s, 1H), 6.19 (t, 1H), 3.61 (m, 2H),3.26 (m, 4H), 3.15 (m, 4H), 2.62 (m, 4H).

EXAMPLE 462A

This example was made by substituting EXAMPLE 457A and(R)-N¹,N¹-dimethyl-4-phenylsulfanyl-butane-1,3-diamine for EXAMPLE 456Cand 2-phenylsulfanylethylamine, respectively, in EXAMPLE 456D.

EXAMPLE 462B

This example was prepared by substituting EXAMPLE 462A for EXAMPLE 456Din EXAMPLE 456E. ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H), 8.19 (d, 1H),7.79 (dd, 1H), 7.49 (m, 5H), 7.37 (m, 4H), 7.24 (m, 3H), 7.18 (t, 2H),7.13 (m, 1H), 6.95 (d, 1H), 6.84 (d, 1H), 6.71 (s, 1H), 4.09 (b, 1H),3.39 (s, 2H), 3.15 (m, 4H), 2.90 (m, 2H), 2.57 (s, 6H), 2.40 (m, 4H),2.08 (b, 2H).

EXAMPLE 463A

This example was made by substituting EXAMPLE 459A and(R)-N¹,N¹-dimethyl-4-phenylsulfanyl-butane-1,3-diamine for EXAMPLE 456Cand 2-phenylsulfanyl-ethylamine, respectively, in EXAMPLE 456D.

EXAMPLE 463B

This example was prepared by substituting EXAMPLE 463A for EXAMPLE 456Din EXAMPLE 456E. ¹H NMR (500 MHz, DMSO-d₆) δ 8.44 (d, 1H), 8.23 (bs,1H), 7.78 (dd, 1H), 7.37 (m, 1H), 7.26 (d, 2H), 7.18 (t, 2H), 7.13 (d,1H), 6.90 (d, 1H), 6.83 (d, 1H), 6.69 (s, 1H), 4.05 (m, 1H), 3.20 (m,4H), 2.49, (s, 6H), 2.00 (m, 2H), 1.39 (m, 4H), 0.93 (s, 6H).

1. A compound of formula (I)

or a therapeutically acceptable salt thereof, wherein A¹ is N or C(A²);one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected from R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹,NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ andN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected from H,F, Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ and C(O)OR^(1A); and Y¹ is H, CN,NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷, OR¹⁷,C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or B¹ and Y¹, togetherwith the atoms to which they are attached, are imidazole or triazole;and one or two or each of A², D¹ and E¹ are independently selected fromR¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹,N(CH₃)C(O)N(CH₃)R¹, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ andN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected from H,F, Cl, Br, I, CF₃, C(O)OH, C(O)NH₂ and C(O)OR^(1A); R¹ is R², R³, R⁴ orR⁵; R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl; R² is phenylwhich is unfused or fused with arene, heteroarene or R^(2A); R^(2A) iscycloalkane or heterocycloalkane; R³ is heteroaryl which is unfused orfused with benzene, heteroarene or R^(3A); R^(3A) is cycloalkane orheterocycloalkane; R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with arene,heteroarene or R^(4A); R^(4A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵ is alkyl, alkenyl or alkynyl,each of which is unsubstituted or substituted with one or two or threesubstituents independently selected from R⁶, R⁷, OR⁷, SR⁷, S(O)R⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷,NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br and I; R⁶ isC₂-C₅-spiroalkyl, each of which is unsubstituted or substituted with OH,(O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂; R⁷ isR⁸, R⁹, R¹⁰ R¹¹; R⁸ is phenyl which is unfused or fused with arene,heteroarene or R^(8A); R^(8A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁹ is heteroaryl which isunfused or fused with arene, heteroarene or R^(9A); R^(9A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three substituents independently selected from R¹², OR¹², NHR¹²,N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br and I; R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶; R¹³ is phenylwhich is unfused or fused with arene, heteroarene or R^(13A); R^(13A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁴ isheteroaryl, each of which is unfused or fused with arene, heteroarene orR^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene, each of which is unfused or fused with arene,heteroarene or R^(15A); R^(15A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁶ is alkyl, alkenyl oralkynyl; R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹; R¹⁸ is phenyl which is unfused orfused with arene, heteroarene or R^(18A);R^(18A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁹ is heteroarylwhich is unfused or fused with arene, heteroarene or R^(19A); R^(19A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three substituents independently selected from R²², OR²², NHR²²,N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br and I; R²² is R²³, R²⁴ or R²⁵; R²³ is phenylwhich is unfused or fused with arene, heteroarene or R^(23A); R^(23A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁴ isheteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(25A); R^(25A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; Z¹ is R²⁶ or R²⁷,each of which is substituted with R²⁸, R²⁹ or R³⁰, each of which issubstituted with CH₂R³⁷, CH(R³¹)(R³⁷), C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷,OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ or N(R³²)R³⁷; R²⁶ is phenyl which isunfused or fused with arene or heteroarene; R²⁷ is heteroaryl which isunfused or fused with arene or heteroarene; R²⁸ is phenyl which isunfused or fused with arene, heteroarene or R^(28A); R^(28A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene R²⁹ isheteroaryl or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁰ is cycloalkyl orcycloalkenyl, each having one or two CH₂ moieties unreplaced or replacedwith independently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NHand one or two CH moieties unreplaced or replaced with N, and each ofwhich is unfused or fused with arene, heteroarene or R^(30A); R^(30A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R³¹and R^(31A) are independently F, Cl, Br or alkyl or are taken togetherand are C₂-C₅-spiroalkyl; R³² is R³³, C(O)R³³ or C(O)OR³³; R³³ is R³⁴ orR³⁵; R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A)is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R³⁵ is alkyl which is unsubstituted or substitutedwith R³⁶; R³⁶ is phenyl which is unfused or fused with arene,heteroarene or R^(36A); R^(36A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁷ is R³⁸, R³⁹ or R⁴⁰, each ofwhich is substituted with R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹,S(O)R⁴¹ or SO₂R⁴¹; R³⁸ is phenyl which is unfused or fused with arene,heteroarene or R^(38A); R^(38A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁹ is heteroaryl which isunfused or fused with arene, heteroarene or R^(39A); R^(39A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁰ isC₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵; R⁴²is phenyl which is unfused or fused with arene, heteroarene or R^(42A);R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴³ is heteroaryl which is unfused or fused witharene, heteroarene or R^(43A); R^(43A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴⁴ is C₃-C₆-cycloalkyl orC₄-C₆-cycloalkenyl, each having one or two CH₂ moieties unreplaced orreplaced with independently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N, and eachof which is unfused or fused with arene, heteroarene or R^(44A); R^(44A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁵is alkyl, alkenyl or alkynyl, each of which is substituted with one ortwo substituents independently selected from R⁴⁶, OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂,C(O)NH₂, C(O)NHR⁴⁶, and C(O)N(R⁴⁶)₂; R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ isphenyl which is unfused or fused with arene, heteroarene or R^(47A);R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁹ isC₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; wherein each foregoing cyclicmoiety is independently unsubstituted, substituted or furthersubstituted with one or two or three or four or five substituentsindependently selected from R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br andI; R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴; R⁵¹ is phenyl which is unfused or fusedwith arene, heteroarene or R^(51A); R^(51A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵² is heteroaryl or R^(52A);R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(53A); R^(53A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁵⁴ is alkyl,alkenyl or alkynyl, each of which is unsubstituted or substituted withone or two or three substituents independently selected from R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br and I; R⁵⁵ is alkyl, alkenyl, alkynyl,phenyl, heteroaryl or R⁵⁶; R⁵⁶ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkyl,each having one or two CH₂ moieties unreplaced or replaced withindependently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and oneor two CH moieties unreplaced or replaced with N.
 2. The compound offormula (I) or therapeutically acceptable salt thereof according toclaim 1, wherein A¹ is N or C(A²); A² is H, F, CN, C(O)OH, C(O)NH₂ orC(O)OR^(1A); B¹ is R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹,OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹,NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹; D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN,NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷, OR¹⁷,C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or B¹ and Y¹, togetherwith the atoms to which they are attached, are imidazole or triazole; R¹is R², R³, R⁴ or R⁵; R^(1A) is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅ -alkyl, C₆-alkyl; R² is phenyl which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole; R³is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole; R⁴is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆ -cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N; R⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl, C₆-alkyl, C₂-alkenyl, C₃-alkenyl, C₄-alkenyl,C₅-alkenyl, C₆-alkenyl, C₃-alkynyl, C₄-alkynyl, C₅-alkynyl orC₆-alkynyl, each of which is unsubstituted or substituted with one ortwo or three substituents independently selected from R⁶, R⁷, OR⁷, SR⁷,S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷,NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br and I; R⁶ is C₂-spiroalkyl, C₃-spiroalkyl,C₄-spiroalkyl or C₅ -spiroalkyl, each of which is unsubstituted orsubstituted with OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂,NH(CH₃) or N(CH₃)₂; R⁷ is R⁸, R⁹, R¹⁰ or R¹¹; R⁸ is phenyl which isunfused or fused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene,triazine, 1,2,3-triazole or R^(8A); R^(8A) is C₄-cycloalkane,C₅-cycloalkane, C₆-cycloalkane, C₄ -cycloalkene, C₅-cycloalkene orC₆-cycloalkene, each having one or two CH₂ moieties unreplaced orreplaced with independently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N; R⁹ isfuranyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;R¹⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆ -cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl,C₈-cycloalkenyl, C₉-cycloalkenyl, or C₁₀-cycloalkenyl, each having oneor two CH₂ moieties unreplaced or replaced with independently selectedO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N; R¹¹ is C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl C₆-alkyl, C₂-alkenyl, C₃-alkenyl, C₄-alkenyl,C₅-alkenyl C₆-alkenyl, C₂-alkynyl, C₃-alkynyl, C₄-alkynyl, C₅-alkynyl orC₆-alkynyl, each of which is unsubstituted or substituted with one ortwo or three substituents independently selected from R¹², OR¹², NHR¹²,N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br and I; R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶; R¹³ is phenylwhich is unfused or fused with benzene, furan, imidazole, isothiazole,isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine, 1,2,3-triazole or R^(13A); R^(13A) isC₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane, C₄-cycloalkene,C₅-cycloalkene or C₆-cycloalkene, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N; R¹⁴ is furanyl, imidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,thienyl, triazinyl, or 1,2,3-triazolyl, each of which is unfused orfused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R¹⁵ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl,C₆-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N; R¹⁶ is C₁-alkyl, C₂-alkyl,C₃-alkyl, C₄-alkyl, C₅-alkyl C₆-alkyl, C₂-alkenyl, C₃-alkenyl,C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₃-alkynyl, C₄-alkynyl, C₅-alkynyl orC₆-alkynyl; R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹; R¹⁸ is phenyl which is unfusedor fused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R¹⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,thienyl, triazinyl or 1,2,3-triazolyl, each of which is unfused or fusedwith benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R²⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl,C₆ -cycloalkyl, C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl,C₁₀-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl,C₇-cycloalkenyl, C₈-cycloalkenyl, C₉-cycloalkenyl, or C₁₀-cycloalkenyl,each having one or two CH₂ moieties unreplaced or replaced withindependently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and oneor two CH moieties unreplaced or replaced with N; R²¹ is C₁-alkyl,C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl, C₂-alkenyl,C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₂-alkynyl, C₃-alkynyl,C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which is unsubstituted orsubstituted with one or two or three substituents independently selectedfrom R²², OR²², NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH,(O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br and I; R²² is R²³, R²⁴or R²⁵; R²³ is phenyl which is unfused or fused with benzene, furan,imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole,oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,thiazole, thiophene, triazine or 1,2,3-triazole; R²⁴ is furanyl,imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl, or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;R²⁵ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆ -cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N; Z¹ is R²⁶ or R²⁷, each of which issubstituted with R²⁸, R²⁹ or R³⁰, each of which is substituted withCH₂R³⁷, CH(R³¹)(R³⁷), C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷,S(O)R³⁷, SO₂R³⁷, NHR³⁷ or N(R³²)R³⁷; R²⁶ is phenyl which is unfused orfused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R²⁷ is furanyl, imidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,thienyl, triazinyl or 1,2,3-triazolyl, each of which is unfused or fusedwith benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R²⁸ is phenyl which is unfused or fused with benzene,furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;R²⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;R³⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆ -cycloalkyl,C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl,C₁₁-cycloalkyl, C₁₂-cycloalkyl, C₁₃-cycloalkyl, C₁₄-cycloalkyl,C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl,C₈-cycloalkenyl, C₉-cycloalkenyl or C₁₀-cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N; R³¹ and R^(31A) are independently F, Cl, Br, C₁-alkyl,C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl or are taken togetherand are C₂-spiroalkyl, C₃ -spiroalkyl, C₄-spiroalkyl or C₅-spiroalkyl;R³² is R³³, C(O)R³³ or C(O)OR³³; R³³ is R³⁴ or R³⁵; R³⁴ is phenyl whichis unfused or fused with benzene, furan, imidazole, isothiazole,isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole; R³⁵ is C₁-alkyl, C₂-alkyl,C₃-alkyl, C₄-alkyl, C₅ -alkyl or C₆-alkyl, each of which isunsubstituted or substituted with R³⁶; R³⁶ is phenyl which is unfused orfused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substitutedwith R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹; R³⁸is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole; R³⁹ is furanyl, imidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each ofwhich is unfused or fused with benzene, furan, imidazole, isothiazole,isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole; R⁴⁰ is C₃-cycloalkyl,C₄-cycloalkyl, C₅-cycloalkyl, C₆ -cycloalkyl, C₇-cycloalkyl,C₈-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl,C₇-cycloalkenyl or C₈-cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N; R⁴¹ isR⁴², R⁴³, R⁴⁴ or R⁴⁵; R⁴² is phenyl which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine, 1,2,3-triazole orR^(42A); R^(42A) is C₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane,C₄-cycloalkene, C₅-cycloalkene or C₆-cycloalkene, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N; R⁴³ is furanyl, imidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,thienyl, triazinyl or 1,2,3-triazolyl, each of which is unfused or fusedwith benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R⁴⁴ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl,C₆ -cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl,each having one or two CH₂ moieties unreplaced or replaced withindependently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and oneor two CH moieties unreplaced or replaced with N, and each of which isunfused or fused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5 -oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R⁴⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl C₆-alkyl, C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenylC₆-alkenyl, C₂-alkynyl, C₃-alkynyl, C₄-alkynyl, C₅-alkynyl orC₆-alkynyl, each of which is substituted with one or two substituentsindependently selected from R⁴⁶, OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂,C(O)NHR⁴⁶, and C(O)N(R⁴⁶)₂; R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ is phenyl whichis unfused or fused with benzene, furan, imidazole, isothiazole,isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole; R⁴⁸ is furanyl, imidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each ofwhich is unfused or fused with benzene, furan, imidazole, isothiazole,isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole; R⁴⁹ is C₃-cycloalkyl,C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₄-cycloalkenyl,C₅-cycloalkenyl or C₆-cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N; whereinthe moieties represented by B¹ and Y¹ together are substituted withC₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl, each ofwhich is substituted with one or two substituents independently selectedfrom SR⁵⁵ and N(R⁵⁵)₂, wherein R⁵⁵ is independently selected fromphenyl, C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl and C₆-alkyl;the moieties represented by R², R³ and R⁴ are unsubstituted orsubstituted with one or two substituents independently selected fromR⁵⁰, OR⁵⁰, SR⁵⁰, SO₂R⁵⁰, CO(O)R⁵⁰ and OCF₃, wherein R⁵⁰ is phenyl,C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl; themoieties represented by R⁸, R⁹ and R¹⁰ are unsubstituted or substitutedwith one or two substituents independently selected from R⁵⁰, OR⁵⁰,C(O)NHSO₂R⁵⁰, CO(O)R⁵⁰, C(O)R⁵⁰, C(O)OH, C(O)NHOH, OH, NH₂, F, Cl, Brand I, wherein R⁵⁰ is phenyl, tetrazolyl or R⁵⁴, wherein R⁵⁴ isC₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl, each ofwhich is unsubstituted or substituted with phenyl; the moietiesrepresented by R²⁶ and R²⁷ are further unsubstituted or substituted withone or two substituents independently selected from F, Br, Cl and I; themoieties represented by R²⁸, R²⁹ and R³⁰ are further unsubstituted orsubstituted with OR⁵⁴, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl or C₆-alkyl, each of which is unsubstituted orsubstituted with R⁵⁶, wherein R⁵⁶ is C₃ -cycloalkyl, C₄-cycloalkylC₅-cycloalkyl or C₆-cycloalkyl, each having one or two CH₂ moietiesreplaced with independently selected O or NH and one CH moietyunreplaced or replaced with N; the moieties represented by R³⁸, R³⁹ andR⁴⁰ are further unsubstituted or substituted with one or twosubstituents independently selected from R⁵⁴, F, Br, Cl and I, whereinR⁵⁴ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl; andthe moieties represented by R⁴², R⁴³, R⁴⁴ and R⁴⁵ are unsubstituted orsubstituted with one or two substituents independently selected fromR⁵⁰, OR⁵⁰, SR⁵⁰, N(R⁵⁰)₂, SO₂R⁵⁰, CN, CF₃, F, Cl, Br and I, wherein R⁵⁰is phenyl or R⁵⁴, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅-alkyl or C₆-alkyl, each of which is unsubstituted or substituted withN(R⁵⁵)₂ or R⁵⁶, wherein R⁵⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄ -alkyl,C₅-alkyl or C₆-alkyl and R⁵⁶ is C₃-cycloalkyl, C₄-cycloalkyl,C₅-cycloalkyl or C₆-cycloalkyl, each having one CH₂ moiety unreplaced orreplaced with independently selected O, C(O), S, S(O), SO₂ or NH and oneor two CH moieties unreplaced or replaced with N.
 3. The compound offormula (I) or therapeutically acceptable salt thereof according toclaim 2, wherein A¹ is C(A²); A² is H, F, CN, C(O)OH, C(O)NH₂ orC(O)OR^(1A); B¹ is R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹,OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹,NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹; D¹ is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN,NO₂, C(O)OH, F, Cl, Br, CF₃, OCF₃, NH₂, C(O)NH₂, or B¹ and Y¹, togetherwith the atoms to which they are attached, are imidazole or triazole; R¹is R², R³, R⁴ or R⁵; R^(1A) is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅ -alkyl, or C₆-alkyl; R² is phenyl which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole; R³is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene; R⁴ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N; R⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅ -alkyl, C₆-alkyl, C₂-alkenyl, C₃-alkenyl, C₄-alkenyl,C₅-alkenyl, C₆-alkenyl, C₃-alkynyl, C₄-alkynyl, C₅-alkynyl orC₆-alkynyl, each of which is unsubstituted or substituted with one ortwo or three substituents independently selected from R⁶, R⁷, OR⁷, SR⁷,S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷,NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br and I; R⁶ is C₂-spiroalkyl, C₃-spiroalkyl,C₄-spiroalkyl or C₅ -spiroalkyl, each of which is unsubstituted orsubstituted with OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂,NH(CH₃) or N(CH₃)₂; R⁷ is R⁸, R⁹, R¹⁰ or R¹¹; R⁸ is phenyl which isunfused or fused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene,triazine, 1,2,3-triazole or R^(8A); R^(8A) is C₄-cycloalkane,C₅-cycloalkane, C₆-cycloalkane, C₄ -cycloalkene, C₅-cycloalkene orC₆-cycloalkene, each having one or two CH₂ moieties unreplaced orreplaced with independently selected O, C(O), S, S(O), SO₂ or NH and oneor two CH moieties unreplaced or replaced with N; R⁹ is furanyl,imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene; R¹⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl,C₁₀-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl,C₇-cycloalkenyl, C₈-cycloalkenyl, C₉-cycloalkenyl, or C₁₀-cycloalkenyl,each having one or two CH₂ moieties unreplaced or replaced withindependently selected O, C(O), CNOCH₃, S, S(O), SO₂ or NH and one ortwo CH moieties unreplaced or replaced with N; R¹¹ is C₁-alkyl,C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl, C₂-alkenyl,C₃-alkenyl, C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₂-alkynyl, C₃-alkynyl,C₄-alkynyl, C₅-alkynyl or C₆-alkynyl, each of which is unsubstituted orsubstituted with one or two or three substituents independently selectedfrom R¹², OR¹², NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH,(O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br and I; R¹² is R¹³, R¹⁵or R¹⁶; R¹³ is phenyl which is unfused or fused with benzene, furan,imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole,oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,thiazole, thiophene, triazine, 1,2,3-triazole or R^(13A); R^(13A) isC₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane, C₄-cycloalkene,C₅-cycloalkene or C₆-cycloalkene, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N; R¹⁴ isfuranyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl, or 1,2,3-triazolyl, each of which is unfused or fused withbenzene; R¹⁵ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N; R¹⁶ is C₁-alkyl, C₂-alkyl,C₃-alkyl, C₄-alkyl, C₅ -alkyl C₆-alkyl, C₂-alkenyl, C₃-alkenyl,C₄-alkenyl, C₅-alkenyl C₆-alkenyl, C₃-alkynyl, C₄-alkynyl, C₅-alkynyl orC₆-alkynyl; Z¹ is R²⁶ or R²⁷, each of which is substituted with R²⁸, R²⁹or R³⁰, each of which is substituted with CH₂R³⁷, C(R³¹)(R^(31A))(R³⁷),C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷ or NHR³⁷; R²⁶ is phenyl which isunfused or fused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R²⁷ is furanyl, imidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,thienyl, triazinyl or 1,2,3-triazolyl, each of which is unfused or fusedwith benzene; R²⁸ is phenyl which is unfused or fused with benzene,furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;R²⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene; R³⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₇-cycloalkyl, C₈-cycloalkyl, C₉-cycloalkyl,C₁₀-cycloalkyl, C₁₁-cycloalkyl, C₁₂-cycloalkyl, C₁₃-cycloalkyl,C₁₄-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl,C₇-cycloalkenyl, C₈-cycloalkenyl, C₉-cycloalkenyl or C₁₀-cycloalkenyl,each having one or two CH₂ moieties unreplaced or replaced withindependently selected O, C(O), S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N; R³¹ and R^(31A) areindependently F, Cl, Br, C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅-alkyl or C₆-alkyl or are taken together and are C₂-spiroalkyl,C₃-spiroalkyl, C₄-spiroalkyl or C₅-spiroalkyl; R³⁷ is R³⁸, R³⁹ or R⁴⁰,each of which is substituted with R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹,SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹; R³⁸ is phenyl which is unfused or fused withbenzene, furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, triazine or 1,2,3-triazole;R³⁹ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene; R⁴⁰ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₇-cycloalkyl, C₈-cycloalkyl, C₄-cycloalkenyl,C₅-cycloalkenyl, C₆-cycloalkenyl, C₇-cycloalkenyl or C₈-cycloalkenyl,each having one or two CH₂ moieties unreplaced or replaced withindependently selected O, C(O), S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N; R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵; R⁴²is phenyl which is unfused or fused with benzene, furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine, 1,2,3-triazole or R^(42A); R^(42A) isC₄-cycloalkane, C₅-cycloalkane, C₆-cycloalkane, C₄-cycloalkene,C₅-cycloalkene or C₆-cycloalkene, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N; R⁴³ isfuranyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl,triazinyl or 1,2,3-triazolyl, each of which is unfused or fused withbenzene; R⁴⁴ is C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₄-cycloalkenyl, C₅-cycloalkenyl or C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with benzene, furan, imidazole, isothiazole, isoxazole,1,2,3-oxadiazole, 1,2,5 -oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazineor 1,2,3-triazole; R⁴⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅-alkyl C₆-alkyl, C₂-alkenyl, C₃-alkenyl, C₄-alkenyl, C₅-alkenylC₆-alkenyl, C₂-alkynyl, C₃-alkynyl, C₄-alkynyl, C₅-alkynyl orC₆-alkynyl, each of which is substituted with one or two substituentsindependently selected from R⁴⁶, OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂,C(O)NHR⁴⁶, and C(O)N(R⁴⁶)₂; R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ is phenyl whichis unfused or fused with benzene, furan, imidazole, isothiazole,isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, triazine or 1,2,3-triazole; R⁴⁸ is furanyl, imidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each ofwhich is unfused or fused with benzene; R⁴⁹ is C₃-cycloalkyl,C₄-cycloalkyl, C₅-cycloalkyl, C₆ -cycloalkyl, C₄-cycloalkenyl,C₅-cycloalkenyl or C₆-cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N; whereinthe moieties represented by B¹ and Y¹ together are substituted withC₂-alkyl, C₃-alkyl or C₄-alkyl, each of which is substituted with one ortwo substituents independently selected from SR⁵⁵ and N(R⁵⁵)₂, whereinR⁵⁵ is independently selected from phenyl and C₁-alkyl; the moietiesrepresented by R², R³ and R⁴ are unsubstituted or substituted with oneor two substituents independently selected from R⁵⁰, OR⁵⁰, SR⁵⁰, SO₂R⁵⁰,CO(O)R⁵⁰ and OCF₃, wherein R⁵⁰ is phenyl, C₁-alkyl, C₂-alkyl, C₃-alkylor C₄ -alkyl; the moieties represented by R⁸, R⁹ and R¹⁰ areunsubstituted or substituted with one or two substituents independentlyselected from R⁵⁰, OR⁵⁰, C(O)NHSO₂R⁵⁰, CO(O)R⁵⁰, C(O)R⁵⁰, C(O)OH,C(O)NHOH, OH, NH₂, F, Cl, Br and I, wherein R⁵⁰ is phenyl, tetrazolyl orR⁵⁴, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl or C₃-alkyl, each of which isunsubstituted or substituted with phenyl; the moieties represented byR²⁶ and R²⁷ are further unsubstituted or substituted with one or twosubstituents independently selected from F, Br, Cl and I; the moietiesrepresented by R²⁸, R²⁹ and R³⁰ are further unsubstituted or substitutedwith OR⁵⁴, wherein R⁵⁴ is C₁-alkyl or C₂-alkyl, each of which isunsubstituted or substituted with N(R⁵⁵)₂ or R⁵⁶, wherein R⁵⁵ isC₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl or C₆-alkyl, and R⁵⁶ isC₅-cycloalkyl or C₆-cycloalkyl, each having one or two CH₂ moietiesreplaced with independently selected O or NH and one CH moietyunreplaced or replaced with N; the moieties represented by R³⁸, R³⁹ andR⁴⁰ are substituted or substituted with one or two substituentsindependently selected from C₁-alkyl, F, Br, Cl and I; and the moietiesrepresented by R⁴², R⁴³, R⁴⁴ and R⁴⁵ are unsubstituted or substitutedwith one or two substituents independently selected from R⁵⁰, OR⁵⁰,SR⁵⁰, N(R⁵⁰)₂, SO₂R⁵⁰, CN, CF₃, F, Cl, Br and I, wherein R⁵⁰ is phenylor R⁵⁴, wherein R⁵⁴ is C₁-alkyl, C₂-alkyl or C₃-alkyl, each of which isunsubstituted or substituted with N(C₁-alkyl)₂ or C₆-cycloalkyl havingone CH₂ moiety replaced with O and one CH moiety replaced with N.
 4. Thecompound of formula (I) or therapeutically acceptable salt thereofaccording to claim 3, wherein A¹ is C(A²); A² is H, F, CN, C(O)OH,C(O)NH₂ or C(O)OCH₃; B¹ is R¹, OR¹, NHR¹, N(R¹¹)₂ or NR¹C(O)N(R¹)₂; D¹is H, F, Cl or CF₃; E¹ is H, F or Cl; Y¹ is H, CN, NO₂, F, Cl, CF₃,OCF₃, NH₂, C(O)NH₂, or B¹ and Y¹, together with the atoms to which theyare attached, are imidazole or triazole; R¹ is phenyl, pyrrolyl,C₅-cycloalkyl, C₆-cycloalkyl, piperidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothiopyranyl or R⁵; R⁵ is C₁-alkyl,C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅ -alkyl or C₆-alkyl, each of which isunsubstituted or substituted with one or two or three substituentsindependently selected from C₄-spiroalkyl, C₄-spiroalkyl, R⁷, OR⁷, SR⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷,NHC(O)OR⁷, NHC(O)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, OH, C(O)OH and NH₂;R⁷ is phenyl, furanyl, imidazolyl, pyridinyl, tetrazolyl, thiazolyl,thienyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl, 1,3-benzothiazole,C₃-cycloalkyl, C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, azetidinyl;morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, thiomorpholinylsulfone 7-azabicyclo[2.2.1]heptanyl, 8 -azabicyclo[3.2.1]-octanyl,4,5-dihydro-1H-imidazolyl 2-oxa-5-azabicyclo-[2.2.1]heptanyl,1,4,5,6-tetrahydropyrimidinyl or R¹¹; R¹¹ is C₁-alkyl, C₂-alkyl,C₃-alkyl or C₄-alkyl, each of which is unsubstituted or substituted withone or two or three substituents independently selected from R¹², OR¹²,N(R¹²)₂, C(O)N(R¹²)₂, OH, C(O)OH, NH₂, CF₃, F, Cl, Br and I; R¹² is1,3-benzodioxolyl, pyridinyl, morpholinyl or C₁-alkyl; Z¹ is phenyl orpyridinyl, each of which is substituted with C₆-cycloalkenyl,piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl oroctahydropyrrolo[3,4-c]pyrrolyl, each of which is substituted withCH₂R³⁷, C(C₂-spiroalkyl)(R³⁷) or C(O)R³⁷; R³⁷ is phenyl, naphthyl,imidazolyl, pyrazolyl, pyridinyl, C₅-cycloalkenyl, C₆-cycloalkenyl,C₇-cycloalkenyl, C₈-cycloalkenyl or 3,6-dihydro-2H-pyranyl, each ofwhich is substituted with R⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹ or SR⁴¹; R⁴¹is phenyl, naphthyl, cyclohexyl, morpholinyl, piperidinyl, thienyl,pyridinyl, quinolinyl, benzofuranyl, 1,3-benzodioxolyl, isoindolinyl,1,3-oxazolidin-2 -onyl or R⁴⁵; R⁴⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl orC₄-alkyl, each of which is substituted with phenyl; wherein the moietiesrepresented by B¹ and Y¹ together are substituted with C₂-alkyl,C₃-alkyl or C₄-alkyl, each of which is substituted with one or twosubstituents independently selected from SR⁵⁵ and N(R⁵⁵)₂, wherein R⁵⁵is independently selected from phenyl and C₁-alkyl; the moietiesrepresented by R¹ are unsubstituted or substituted with one or twosubstituents independently selected from R⁵⁰, OR⁵⁰, SR⁵⁰, SO₂R⁵⁰,CO(O)R⁵⁰ and OCF₃, wherein R⁵⁰ is phenyl, C₁-alkyl, C₂-alkyl, C₃-alkylor C₄ -alkyl; the moieties represented by R⁷ are unsubstituted orsubstituted with one or two substituents independently selected fromR⁵⁰, OR⁵⁰, C(O)NHSO₂R⁵⁰, CO(O)R⁵⁰, C(O)R⁵⁰, C(O)OH, C(O)NHOH, OH, NH₂,F, Cl, Br and I, wherein R⁵⁰ is phenyl, tetrazolyl or R⁵⁴, wherein R⁵⁴is C₁-alkyl, C₂-alkyl or C₃-alkyl, each of which is unsubstituted orsubstituted with phenyl; the phenyl and pyridinyl moieties of Z¹ arefurther unsubstituted or substituted with one or two substituentsindependently selected from F, Br, Cl and I; the C₆-cycloalkenyl,piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl andoctahydropyrrolo[3,4-c]pyrrolyl moieties of Z¹ are further unsubstitutedor substituted with OR⁵⁴, wherein R⁵⁴ is C₁-alkyl or C₂-alkyl, each ofwhich is unsubstituted or substituted with N(C₁-alkyl)₂, morpholinyl,piperidinyl or piperidinyl; the moieties represented by R³⁷ are furtherunsubstituted or substituted with one or two substituents independentlyselected from C₁-alkyl, F, Br, Cl and I; and the moieties represented byR⁴¹ are unsubstituted or substituted with one or two substituentsindependently selected from R⁵⁰, OR⁵⁰, SR⁵⁰, N(R⁵⁰)₂, SO₂R⁵⁰, CN, CF₃,F, Cl, Br and I, wherein R⁵⁰ is phenyl or R⁵⁴, wherein R⁵⁴ is C₁-alkyl,C₂-alkyl or C₃-alkyl, each of which is unsubstituted or substituted withN(C₁-alkyl)₂ or morpholinyl.